piperidines and Ovarian-Neoplasms

The standard of care for newly diagnosed advanced ovarian cancer is surgical cytoreduction plus platinum-based chemotherapy; however, recurrent disease frequently occurs after treatment. Poly(ADP-ribose) polymerase (PARP) inhibitors as first-line maintenance therapy have been demonstrated to significantly reduce the risk of disease progression or death in patients with advanced ovarian cancer who have a complete or partial response to first-line platinum-based chemotherapy. Niraparib is the only PARP inhibitor that offers a significant progression-free survival benefit compared with placebo in this patient population regardless of the homologous recombination status. However, predictive factors for treatment responses and approaches to dose optimization remain to be investigated. In this study, two Chinese patients with newly diagnosed advanced ovarian cancer exhibited long-term responses to niraparib treatment, and hematological toxicity was successfully managed by dose adjustment. The literature on clinical trials and real-world experience on the efficacy, tolerability, and dose individualization of niraparib treatment in Western and Chinese patients was also reviewed. Future research is warranted to identify the characteristics of 'long responders' to niraparib treatment.

Topics: Asian People; Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

PARP inhibitors are effective in different types of tumors such as ovarian, breast, prostate and pancreatic cancer. Many studies are in progress and may lead to prescription evolution. PARP inhibitors prescription is almost reserved to patients with a constitutional BRCA mutation or a somatic BRCA alteration or a tumor with a deficiency in homologous recombination. Nowadays, the diagnosis of homologous recombination deficit, HRD, is possible with the prescription of a myChoice CDx (Myriad) test. PARP inhibitors are studied in association with chemotherapy and targeted therapies but also with radiotherapy and with immune checkpoint inhibitors. Access to PARP inhibitors is challenged with the emergence of resistance mechanism. Various trials are now studying the possibility of reversing these resistance mechanisms.

Topics: Breast Neoplasms; DNA Damage; DNA Repair-Deficiency Disorders; Drug Resistance, Neoplasm; Female; Genes, BRCA1; Genes, BRCA2; Homologous Recombination; Humans; Indazoles; Indoles; Male; Ovarian Neoplasms; Pancreatic Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms; Recombinational DNA Repair

New molecular therapeutic approaches have emerged in recent years for advanced gynaecological cancers, including targeted therapies such as poly-ADP-ribose polymerase inhibitors (PARPi). These have demonstrated efficacy in high-grade serous ovarian cancers in patients carrying a mutation in the BRCA gene, which predisposes them to breast and ovarian cancers. Clinical and pre-clinical data suggest that the activity of PARPi inhibitors may not be limited to BRCA mutated tumours and may involve the homologous recombination pathway. These data raise the question of the potential efficacy of PARPi in advanced endometrial and cervical cancers where treatment options are currently limited. At present, there are few data available on the activity of PARPi in endometrial and cervical cancers, but some results seem promising. In this review, we present a synthesis of the available studies concerning PARPi in endometrial and cervical cancer.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Clinical Trials as Topic; DNA Damage; DNA Repair-Deficiency Disorders; Endometrial Neoplasms; Female; Humans; Indazoles; Indoles; Ovarian Neoplasms; Papillomavirus Infections; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Uterine Cervical Neoplasms

Patients with epithelial ovarian cancer (EOC), treated with niraparib maintenance, present with haematological and gastrointestinal toxicities. Limited data exist on niraparib safety assessment.. To evaluate niraparib safety profile, as maintenance therapy, in women with platinum-sensitive EOC.. PubMed and Cochrane searches were carried out up to April 2021 for randomised controlled trials (RCTs) evaluating niraparib versus placebo in EOC patients with a response to platinum-based chemotherapy. Regarding the meta-analysis, for dichotomous data, the pooled risk ratio (RR) was calculated.. A total of 1539 patients from three RCTs revealed that niraparib-treated patients are associated with a significantly higher risk of any grade of nausea (RR, 2.15; 95% CI, 1.86 to 2.48), fatigue (RR, 1.26; 95% CI, 1.05 to 1.52,. Niraparib is considered an effective and well-tolerated choice, with an improved safety profile, for the maintenance treatment of EOC patients.

Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines

Poly (adenosine diphosphate)-ribose polymerase (PARP) inhibitors for tumors with homologous recombination deficiency (HRD), including pathogenic mutations in. JGOG2052 is a single-arm, open-label, multi-center, phase 2 clinical trial to evaluate the efficacy and safety of niraparib monotherapy for a recurrent or persistent rare fraction of gynecologic malignancies with. Japan Primary Registries Network (JPRN) Identifier: jRCT2031210264.

Topics: Clinical Trials, Phase II as Topic; Female; Genital Neoplasms, Female; Homologous Recombination; Humans; Indazoles; Ovarian Neoplasms; Piperidines

We reviewed clinical data for niraparib monotherapy in

Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Quality of Life

Niraparib (Zejula™) is a PARP inhibitor which is approved for maintenance therapy in adults with advanced ovarian cancer in complete or partial response to platinum-based chemotherapy. In a placebo-controlled phase III trial in patients with newly diagnosed advanced ovarian cancer, niraparib significantly extended progression free survival in two predefined populations, namely a patient population with altered homologous-recombination DNA repair pathways [i.e. homologous-recombination deficiency positive (HRd)] and the overall trial population. A prespecified exploratory subgroup analysis indicated that niraparib was also efficacious in patients who were homologous recombination deficiency negative or homologous recombination proficient (HRp). Niraparib has a manageable tolerability profile with myelosuppression as the main safety concern. Haematological reactions were managed with monitoring and dose reduction or interruption. A weight- and platelet count-based individualised dosage regimen introduced during the trial (and subsequently approved) appeared to improve haematological tolerability. Niraparib is a useful option for first-line maintenance therapy for advanced ovarian cancer in adults who responded to platinum-based chemotherapy, regardless of homologous-recombination deficiency status and is a promising option for HRp patients, for whom maintenance treatment options are limited.. In 2021, ovarian cancer is predicted to be responsible for ≈ 43,770 deaths in Europe and the USA combined. Niraparib (Zejula™) is a once-daily oral treatment for first-line maintenance therapy in adults with advanced ovarian cancer that is responsive to chemotherapy. Although other agents of the same drug class (e.g. olaparib) are only approved for use against tumours with compromised DNA repair mechanisms, niraparib is approved without this restriction. Niraparib reduced the risk of disease progression or death in patients with newly diagnosed ovarian cancer, irrespective of whether the patients had compromised or functional DNA repair mechanisms. Abnormal blood counts are the main safety concern with niraparib, though adverse drug reactions may be managed through monitoring and interrupting or decreasing the dosage. Starting treatment at a personalised lower dosage may also reduce the likelihood of adverse drug reactions. Niraparib is a useful option for first-line maintenance therapy for advanced ovarian cancer, regardless of the patient's DNA repair mechanisms, and is a promising option for patients with functional DNA repair mechanisms, a group for which maintenance treatment options are limited.

Topics: Adult; Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Maintenance Chemotherapy; Ovarian Neoplasms; Piperidines

In early stages, standard treatment is adjuvant chemotherapy, consisting of platinum-based combination for 6 cycles, especially in serous and endometrioid high grade carcinomas. In advanced stages, indication of neoadjuvant chemotherapy must be discussed on a case-by-case basis in multidisciplinary meetings (MDM). Bevacizumab can also be considered in the neoadjuvant setting in some circumstances, always after discussion in MDM. Carboplatin plus paclitaxel every 21 days, with or without bevacizumab remains the standard of care for first-line chemotherapy. Inhibitors of poly-(ADP-riboses) polymerases (PARPi) have been approved and are reimbursed as maintenance monotherapy in tumors carrying BRCA1 or BRCA2 mutation after complete or partial response to chemotherapy. Two recent studies demonstrated the efficacy of PARPi on progression free survival, one for niraparib single-agent in patients with high-grade ovarian carcinoma regardless of BRCA status, the other one for the combination of bevacizumab and olaparib in patients with high grade carcinoma, with positive test for homologous recombination DNA repair deficiency (regardless of BRCA status). These two new modalities of maintenance therapy are now available in compassionate use programs or post compassionate use programs. Depending on pending decisions upon reimbursement, these indications might be somewhat modified.

Topics: Algorithms; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Carcinoma, Ovarian Epithelial; Chemotherapy, Adjuvant; Drug Administration Schedule; Female; Genes, BRCA1; Genes, BRCA2; Humans; Indazoles; Maintenance Chemotherapy; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Staging; Ovarian Neoplasms; Paclitaxel; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

The standard treatment for advanced ovarian cancer is cytoreductive surgery followed by cytotoxic chemotherapy. However, it has high risk of recurrence and poor prognosis. Poly(ADPribose) polymerase (PARP) inhibitors selectively target DNA double-strand breaks (DSBs) in tumor cells that cannot be repaired and induce the synthetic lethality of BRCA1/2 mutation cancers. PARP inhibitors are clinically used to treat recurrent ovarian cancer and show significant efficacy in ovarian cancer patients with homologous recombination repair (HRR) pathway defects. PARP inhibitors also have significant clinical benefits in patients without HR defects. With the increasingly extensive clinical application of PARP inhibitors, the possibility of acquiring drug resistance is high. Therefore, clinical strategies should be adopted to manage drug resistance of PARP inhibitors. This study aims to summarize the indications and toxicity of PARP inhibitors, the mechanism of action, targeted treatment of drug resistance, and potential methods to manage drug-resistant diseases. We used the term "ovarian cancer" and the names of each PARP inhibitor as keywords to search articles published in the Medical Subject Headings (MeSH) on Pubmed, along with the keywords "clinicaltrials.gov" and "google.com/patents" as well as "uspto.gov." The FDA has approved olaparib, niraparib, and rucaparib for the treatment of recurrent epithelial ovarian cancer (EOC). Talazoparib and veliparib are currently in early trials and show promising clinical results. The mechanism underlying resistance to PARP inhibitors and the clinical strategies to overcome them remain unclear. Understanding the mechanism of resistance to PARP inhibitors and their relationship with platinum resistance may help with the development of antiresistance therapies and optimization of the sequence of drug application in the future clinical treatment of ovarian cancer.

Topics: Antineoplastic Agents; Benzimidazoles; BRCA1 Protein; BRCA2 Protein; Carcinoma, Ovarian Epithelial; DNA Repair; Drug Resistance, Neoplasm; Female; Humans; Indazoles; Indoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases

To summarize the data supporting the use of maintenance therapy in ovarian cancer treatment.. Since December 2016, the United States Food and Drug Administration has approved four drugs for six different ovarian cancer maintenance indications based on the results of clinical trials demonstrating efficacy and tolerability. These include antiangiogenesis and poly (adenosine diphosphate-ribose) inhibitors (PARP inhibitors). Four drugs are approved for use in maintenance therapy for recurrent ovarian cancer, including bevacizumab (GOG-0213 and OCEANS), niraparib (NOVA), olaparib (Study 19 and SOLO2) and rucaparib (ARIEL3). Two drugs are approved for use in maintenance therapy in newly diagnosed ovarian cancer, including bevacizumab (GOG-0218) and olaparib (SOLO1). New data were reported at the European Society for Medical Oncology Congress in October 2019 that may lead to the approval of additional strategies in front-line maintenance, including the use of niraparib (PRIMA), veliparib (VELIA) and bevacizumab + olaparib (PAOLA).. The landscape of maintenance treatment options for ovarian cancer has been rapidly expanding and continues to evolve as new data emerge. Currently approved strategies include antiangiogenesis and PARP inhibitor treatments.

Topics: Angiogenesis Inhibitors; Bevacizumab; Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Indoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic

To review the efficacy and safety of niraparib for the treatment of recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer (OC, FTC, and PPC).. A literature search via MEDLINE through PubMed from August 2013 to January 2020 was performed using the key terms. Completed and ongoing trials were identified through a review of the website trial registry https://www.clinicaltrials.gov.. In a phase III, double-blind clinical trial, progression-free survival improved in patients treated with niraparib compared with placebo as maintenance treatment for patients with platinum-sensitive, recurrent OC: 21 versus 5.5 months in the germline breast cancer susceptibility gene (. Poly (ADP-ribose) polymerase (PARP) inhibitors have gained a place in the therapeutic management of OC, FTC, and PPC because of their ability to suppress growth of homologous recombination deficiency-positive tumors, including those with. PARP inhibitors can be used as a single agent for maintenance therapy for platinum-sensitive recurrent disease in patients with partial or complete response following 2 or more rounds of platinum-based therapy.

Topics: Carcinoma, Ovarian Epithelial; Clinical Trials, Phase III as Topic; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival

The use of poly (ADP-ribose) polymerase (PARP) inhibitors in the front-line management of advanced ovarian cancer has recently emerged as an exciting strategy with the potential to improve outcomes for patients with advanced ovarian cancer. In this article, we review the results of four recently published Phase III randomised controlled trials evaluating the use of PARP inhibitors in the primary treatment of ovarian cancer (SOLO1, PRIMA, PAOLA-1, and VELIA). Collectively, the studies suggest that PARP maintenance in the upfront setting is most beneficial among patients with BRCA-associated ovarian cancers (hazard ratios range from 0.31 to 0.44), followed by patients with tumours that harbour homologous recombination deficiencies (hazard ratios range from 0.33 to 0.57). All three studies that included an all-comer population were able to demonstrate benefit of PARP inhibitors, regardless of biomarker status. The FDA has approved olaparib for front-line maintenance therapy among patients with BRCA-associated ovarian cancers, and niraparib for all patients, regardless of biomarker status. In determining which patients should be offered front-line maintenance PARP inhibitors, and which agent to use, there are multiple factors to consider, including FDA indication, dosing preference, toxicity, risks versus benefits for each patient population, and cost. There are ongoing studies further exploring the front-line use of PARP inhibitors, including the potential downstream effects of PARP-inhibitor resistance in the recurrent setting, combining PARP-inhibitors with other anti-angiogenic drugs, immunotherapeutic agents, and inhibitors of pathways implicated in PARP inhibitor resistance.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Drug Approval; Drug Costs; Drug Resistance, Neoplasm; Female; Humans; Indazoles; Maintenance Chemotherapy; Mutation; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Progression-Free Survival; Randomized Controlled Trials as Topic; Recombinational DNA Repair; United States; United States Food and Drug Administration

Breast and ovarian cancer are common malignancies among older adults, causing significant morbidity and mortality. Although most cases of breast and ovarian cancer are sporadic, a significant proportion is caused by mutations in cancer susceptibility genes, most often breast cancer susceptibility genes (BRCA) 1 and 2. Furthermore, some breast and ovarian tumors are phenotypically similar to those with BRCA mutations, a phenomenon known as "BRCAness". BRCA mutations and "BRCAness" lead to defects in DNA repair, which may be a target for therapeutic agents such as Poly ADP-Ribose Polymerase (PARP) inhibitors. PARP inhibitors are novel medications which lead to double-strand breaks resulting in cell death due to synthetic lethality, and which have been shown to be effective in patients with advanced breast and ovarian cancers with or without BRCA mutations. Three different PARP inhibitors (olaparib, niraparib, and rucaparib) have been approved for the treatment of ovarian cancer and one (olaparib) for breast cancer harboring BRCA mutations. Here, we review the currently available evidence regarding the use of PARP inhibitors for the treatment of patients with breast and ovarian cancer, with a particular focus on the inclusion of older adults in clinical trials of these therapies. Additionally, we provide an overview of currently ongoing studies of PARP inhibitors in breast and ovarian cancer, and include recommendations for increasing the evidence-base for using these medications among older patients.

Topics: Aged; Aged, 80 and over; Breast Neoplasms; DNA Repair; Female; Genes, BRCA1; Genes, BRCA2; Humans; Indazoles; Indoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Synthetic Lethal Mutations

Poly (ADP-ribose) polymerase (PARP) inhibitors have provided great clinical benefits to ovarian cancer patients. To date, three PARP inhibitors, namely, olaparib, rucaparib and niraparib have been approved for the treatment of ovarian cancer in the United States. Homologous recombination deficiency (HRD) and platinum sensitivity are prospective biomarkers for predicting the response to PARP inhibitors in ovarian cancers. Preclinical data have focused on identifying the gene aberrations that might generate HRD and induce sensitivity to PARP inhibitors in vitro in cancer cell lines or in vivo in patient-derived xenografts. Clinical trials have focused on genomic scar analysis to identify biomarkers for predicting the response to PARP inhibitors. Additionally, researchers have aimed to investigate mechanisms of resistance to PARP inhibitors and strategies to overcome this resistance. Combining PARP inhibitors with HR pathway inhibitors to extend the utility of PARP inhibitors to BRCA-proficient tumours is increasingly foreseeable. Identifying the population of patients with the greatest potential benefit from PARP inhibitor therapy and the circumstances under which patients are no longer suited for PARP inhibitor therapy are important. Further studies are required in order to propose better strategies for overcoming resistance to PARP inhibitor therapy in ovarian cancers.

Topics: Drug Resistance, Neoplasm; Female; Humans; Indazoles; Indoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases

Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce tumour-specific vulnerabilities that can be exploited therapeutically. In 2009, a first-in-man clinical trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib clinically validated the synthetic lethal interaction between inhibition of PARP1, a key sensor of DNA damage, and BRCA1/BRCA2 deficiency. In this review, we summarize a decade of PARP inhibitor clinical development, a work that has resulted in the registration of several PARP inhibitors in breast (olaparib and talazoparib) and ovarian cancer (olaparib, niraparib and rucaparib, either alone or following platinum chemotherapy as maintenance therapy). Over the past 10 years, our knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and we summarise this work here. We also discuss opportunities for expanding the precision medicine approach with PARP inhibitors, identifying a wider population who could benefit from this drug class. This includes developing and validating better predictive biomarkers for patient stratification, mainly based on homologous recombination defects beyond BRCA1/BRCA2 mutations, identifying DNA repair deficient tumours in other cancer types such as prostate or pancreatic cancer, or by designing combination therapies with PARP inhibitors.

Topics: BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Female; Genomic Instability; Humans; Indazoles; Indoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors

Niraparib is an oral poly(ADP ribose) polymerase (PARP) inhibitor that is currently approved by the United States Food and Drug Administration (US FDA) as well as recently approved by the European Medicines Agency (EMA) for the maintenance treatment of women with recurrent ovarian cancer who are in complete or partial response to platinum-based chemotherapy. The mechanisms of action of niraparib include inhibition of PARP enzymatic activity as well as increased formation of PARP-DNA complexes through "trapping" the PARP enzyme on damaged DNA. Phase I and III studies have demonstrated activity and benefit of niraparib in both BRCA mutated (BRCAm) and BRCA wild-type (BRCAwt) cancers. Phase I testing of niraparib established the maximally tolerated dose of 300mg by mouth (PO) daily, and the phase 3 ENGOT-OV16/NOVA study demonstrated the benefit of niraparib maintenance therapy compared to placebo after completion of and response to platinum-based chemotherapy in both BRCAm and BRCAwt ovarian cancer patient populations. Toxicities seen with niraparib include hematologic, gastrointestinal, fatigue, and cardiovascular. Hematologic toxicities include thrombocytopenia, anemia, neutropenia and leukopenia; upfront dose modification to 200mg niraparib for patients with baseline weight of ≤77kg and/or baseline platelets of ≤150,000K/uL should be considered to avoid significant hematologic toxicity, especially thrombocytopenia, based on recent analyses of the ENGOT-OV16/NOVA study. Cardiovascular toxicities include hypertension, tachycardia, as well as palpitations, and patients should be monitored for hypertension. PARP inhibitors have been associated with low risks of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and the overall risk of AML and MDS is 0.9% of all patients treated with niraparib. Niraparib testing is ongoing in newly diagnosed ovarian cancer patients as maintenance therapy following completion of platinum-based chemotherapy, in BRCAwt cancers as treatment, as well as in combinations with other biologic drugs such as immunotherapy and anti-angiogenic agents.

Topics: Carcinoma, Ovarian Epithelial; Clinical Trials as Topic; Female; Humans; Indazoles; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Ovarian cancer is a disease with a propensity to recur despite dramatic responses to initial treatment, which typically consists of a combination of cytoreductive surgery and platinum-based chemotherapy. A maintenance therapy, which may prevent or delay relapse while not negatively impacting quality of life, is critical to improving outcomes. Areas covered: This review discusses the pharmacologic properties, clinical efficacy, and safety profile of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Expert opinion: Following presentation of ENGOT-OV16/NOVA at the European Society for Medical Oncology (ESMO) 2016 Congress, niraparib became the first PARP inhibitor to receive full approval by the U.S. Food and Drug Administration (FDA) for the maintenance treatment of recurrent ovarian cancer, regardless of a patient's germline or somatic mutational status. This approval has had a sweeping impact on treatment strategies, moving the indication for a PARP inhibitor earlier in the treatment course and greatly expanding the population of patients who may benefit from this class of drugs. Active clinical trials suggest that new indications and novel treatment combinations are eagerly sought.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Quality of Life

Niraparib, an orally available selective inhibitor of poly(adenosine diphosphate-ribose) polymerase (PARP), is the first PARP inhibitor approved for use in patients with ovarian cancer who do not harbor a germ-line or somatic mutation in the breast cancer gene (BRCA). Overall, niraparib is well tolerated and its toxicities, primarily hematologic, are manageable especially with recently released initial dose modification guidelines based on weight and baseline platelet count. The role of niraparib as maintenance following frontline platinum-based chemotherapy as well as in the treatment of recurrent high-grade serous ovarian cancer is an active area of investigation. Areas covered: This review focuses on niraparib, its pharmacology, clinical efficacy, and adverse effects as evidenced by prospective clinical trials, and licensed indications. Expert commentary: Niraparib introduced the use of PARP inhibitors regardless of biomarker status. Recent studies highlight the critical need for more accurate biomarkers to identify patients most likely to benefit from treatment with PARP inhibitors. In the next 5 years, we anticipate further expansion of and elucidation regarding the optimal indication for use of niraparib in the treatment of ovarian cancer.

Topics: Biomarkers, Tumor; Dose-Response Relationship, Drug; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Practice Guidelines as Topic

Topics: Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

This is an update of a previously published version of the review (Issue 10, 2011).Epithelial ovarian cancer (EOC) is the seventh most common cause of cancer death among women worldwide. Treatment consists of a combination of surgical debulking and platinum-based chemotherapy. Between 55% and 75% of women who respond to first-line therapy experience relapse within two years. Second-line chemotherapy is palliative and aims to reduce symptoms and prolong survival. Improved understanding about the molecular basis of EOC has led to the development of novel agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and anti-EGFR antibodies.. To compare the effectiveness and harmful effects of interventions that target the epidermal growth factor receptor in the treatment of epithelial ovarian cancer (EOC).. We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2010, Issue 4), MEDLINE, and Embase up to October 2010. We also searched registers of clinical trials, abstracts of scientific meetings, and reference lists of included studies, and we contacted experts in the field. This update includes further searches up to September 2017.. Randomised controlled trials (RCTs) comparing anti-EGFR agents with or without conventional chemotherapy versus conventional chemotherapy alone or no treatment in women with histologically proven EOC.. Two review authors independently abstracted data, assessed risk of bias, and performed GRADE assessment.. From 6105 references obtained through the literature search and an additional 15 references derived from grey literature searches, we identified seven RCTs that met our inclusion criteria and included 1725 participants. Trial results show that after first-line chemotherapy is provided, maintenance treatment with erlotinib (EGFR tyrosine kinase inhibitor (TKI)) probably makes little or no difference in overall survival (hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.81 to 1.20; one study; 835 participants; low-certainty evidence) and may make little or no difference in progression-free survival (HR 1.05, 95% CI 0.90 to 1.23; one study; 835 participants; very low-certainty evidence). Less than 50% of participants provided quality of life data, and study authors reported these results incompletely. The certainty of evidence is very low, but treatment may reduce quality of life compared to observation.Treatment with an EGFR TKI (vandetanib) for women with relapsed EOC may make little or no difference in overall survival (HR 1.25, 95% CI 0.80 to 1.95; one study; 129 participants; low-certainty evidence) and may make little or no difference in progression-free survival (HR 0.99, 95% CI 0.69 to 1.42; one study; 129 participants; very low-certainty evidence). In treating patients with relapse, giving EGFR TKI may slightly increase some toxicities, such as severe rash (risk ratio (RR) 13.63, 95% CI 0.78 to 236.87; one study; 125 participants; very low-certainty evidence). Quality of life data were not available for meta-analysis.Anti-EGFR antibody treatment in relapsed EOC may or may not make a difference to overall survival (HR 0.93, 95% CI 0.74 to 1.18; four studies; 658 participants; moderate-certainty evidence) and may or may not have any effect on progression-free survival (HR 0.90, 95% CI 0.70 to 1.16; four studies; 658 participants; low-certainty evidence). Anti-EGFR antibody treatment may or may not increase side effects, including severe nausea and/or vomiting (RR 1.27, 95% CI 0.56 to 2.89; three studies; 503 participants; low-certainty evidence), severe fatigue (RR 1.06, 95% CI 0.66 to 1.73; I² = 0%; four studies; 652 participants; low-certainty evidence), and hypokalaemia (RR 2.01, 95% CI 0.80 to 5.06; I² = 0%; three studies; 522 participants; low-certainty evidence). Severe diarrhoea rates were heterogeneous across studies (RR 2.87, 95% CI 0.59 to 13.89; four studies; 652 participants; low-certainty evidence), and subgroup analysis revealed tha. Current evidence suggests that an anti-EGFR single-agent biological treatment (EGFR TKI or anti-EGFR antibody) makes little or no difference to survival, either as maintenance treatment after first-line chemotherapy or in association with chemotherapy in recurrent cancer. Anti-EGFR therapy may increase some side effects and may or may not reduce quality of life.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Deoxycytidine; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Progression-Free Survival; Quality of Life; Quinazolines; Randomized Controlled Trials as Topic

Use of poly(ADP-ribose) polymerase (PARP) inhibitors has greatly increased over the past 5 years. With several new Food and Drug Administration (FDA) approvals, three PARP inhibitors have entered into standard of care treatment for epithelial ovarian cancer (including ovarian, fallopian tube, and primary peritoneal cancer). Olaparib and rucaparib currently have indications for treatment of recurrent BRCA mutant ovarian cancer. Olaparib, rucaparib, and niraparib all have indications for maintenance therapy in recurrent platinum-sensitive ovarian cancer after response to platinum-based therapy. In our practice, we use both olaparib and rucaparib in the recurrent setting, and all three PARP inhibitors in the maintenance setting. Choice of which PARP inhibitor to use in either setting is largely based upon baseline laboratory values, number of prior therapies, and presence of a BRCA mutation and/or homologous recombination deficiency (HRD). As (HRD) and other biomarker assessments continue to improve, we anticipate being able to better identify which patients might most benefit from PARP inhibitor therapy in the future. The clinically available PARP inhibitors are currently undergoing extensive investigations in clinical trials. Other newer agents such as talazoparib, veliparib, 2X-121, and CEP-9722 are in earlier stages of development. As more FDA-approved indications for PARP inhibitor therapy in ovarian cancer become available, we anticipate the decision of which PARP inhibitor to use will become increasingly complex.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; BRCA1 Protein; BRCA2 Protein; Carbazoles; Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Indoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Ovary; Phthalazines; Phthalimides; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; 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Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Clinical investigation of poly(ADP-ribose) polymerase (PARP) inhibitors for ovarian cancer treatment has rapidly evolved from observations of single-agent in vitro activity of these agents in BRCA-deficient cancer cells in 2005 to the initiation of multiple phase III studies in 2013. With clinical trial design and treatment of ovarian cancer increasingly based on histological and molecular characteristics, PARP inhibitors are on the horizon of becoming the first biologic agents to be used to treat ovarian cancer based upon pre-selection characteristics of the patient's cancer. PARP inhibitors are most active in ovarian cancers that have defects or aberrations in DNA repair; use of these agents has been of particular interest in high grade serous cancers (HGSC), where studies have shown that ~50% of HGSC have abnormalities of DNA repair through BRCA germline and somatic mutation, post-translational changes of BRCA, and abnormalities of other DNA repair molecules. In addition, as aberrant DNA pathways in other histological subtypes of ovarian cancer are identified, and through the combination of PARP inhibitors with other biologic agents, the pool of eligible patients who may benefit from PARP inhibitors will likely expand. Pending review by the Food and Drug Administration (FDA) and the outcome of confirmatory phase III studies, PARP inhibitors could become the first FDA-approved biologic agent for ovarian cancer and also the first new FDA-approval in ovarian cancer since carboplatin and gemcitabine were approved for platinum sensitive ovarian cancer in 2006. This review discusses the PARP inhibitors that are currently in testing for ovarian cancer treatment and the future of this class of anti-cancer agents.

Topics: Antineoplastic Agents; Benzimidazoles; DNA Repair; Female; Genes, BRCA1; Genes, BRCA2; Humans; Indazoles; Indoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Given the expanding clinical use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis), there is a significant need for optimal strategies with which to treat patients whose cancer progresses while using a PARPi. However, the treatment consensus after PARPi has not been established. The aim of the Korean Gynecologic Oncology Group (KGOG) 3056/NIRVANA-R trial is to investigate the efficacy of niraparib in combination with bevacizumab as a maintenance therapy in platinum-sensitive ovarian cancer patients who were previously treated with a PARPi.. The KGOG 3056/NIRVANA-R is a multi-centre, investigator-initiated, single-arm, phase II trial of patients with platinum-sensitive recurrent ovarian cancer recruited from seven KGOG sites. This study included patients with platinum-sensitive recurrent epithelial ovarian cancer who received at least 2 previous courses of platinum-containing therapy and had been treated with a PARPi. Mucinous histology type was excluded. Patients who had responded to the last platinum regimen (either complete or partial response) were eligible to participate in this study. Forty-four patients will be recruited. All enrolled patients are treated with niraparib and bevacizumab for maintenance therapy until disease progression, unacceptable toxicity, or withdrawal of patient consent. The primary endpoint of the study is 6-month progression-free survival rate. Accrual is expected to be completed in 2022, followed by presentation of results in 2023.. ClinicalTrials.gov Identifier: NCT04734665.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Platinum; Poly(ADP-ribose) Polymerase Inhibitors; Republic of Korea

To evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer at high risk of recurrence.. Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible residual disease [VRD]) in the intent-to-treat population.. In PRIMA (N = 733), 236 (32.2%) patients underwent PDS, and 481 (65.6%) received NACT/IDS before enrollment. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) for progression were similar in PDS (13.7 vs 8.2 months; HR, 0.67 [0.47-0.96]) and NACT/IDS (14.2 vs 8.2 months; HR, 0.57 [0.44-0.73]) subgroups. In patients who received NACT/IDS and had NVRD (n = 304), the hazard ratio (95% CI) for progression was 0.65 (0.46-0.91). In patients with VRD following PDS (n = 183) or NACT/IDS (n = 149), the hazard ratios (95% CI) for progression were 0.58 (0.39-0.86) and 0.41 (0.27-0.62), respectively. PFS was not evaluable for patients with PDS and NVRD because of sample size (n = 37).. In this post hoc analysis, niraparib efficacy was similar across PDS and NACT/IDS subgroups. Patients who had NACT/IDS and VRD had the highest reduction in the risk of progression with niraparib maintenance.

Topics: Carcinoma, Ovarian Epithelial; Chemotherapy, Adjuvant; Cytoreduction Surgical Procedures; Female; Humans; Indazoles; Neoadjuvant Therapy; Neoplasm Staging; Neoplasm, Residual; Ovarian Neoplasms; Piperidines

To assess safety and efficacy of niraparib + bevacizumab as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer.. This multicenter, phase II, single-arm, open-label study enrolled adult patients with stage IIIB to IV ovarian, fallopian tube, or primary peritoneal cancer (NCT03326193). Patients were required to have an attempt at debulking surgery and have a complete response, partial response, or no evidence of disease following first-line, platinum-based chemotherapy with ≥3 cycles of bevacizumab. The primary endpoint was the progression-free survival (PFS) rate at 18 months. Secondary endpoints included PFS, overall survival, and safety.. Among the 105 evaluable patients, the PFS rate at 18 months was 62% (95% CI 52-71%) in the overall population and 76% (95% CI 61-87) in the homologous recombination deficient (HRd), 47% (95% CI 31-64%) in the HR proficient (HRp), and 56% (95% CI 31-79%) in the HR not determined (HRnd) subgroups (December 24, 2020, cutoff). After a median follow-up time of 28.7 months (IQR, 23.9-32.5 months), median PFS was 19.6 months (95% CI 16.5-25.1) in the overall population (N = 105) and 28.3 months (95% CI 19.9-NE), 14.2 months (95% CI 8.6-16.8), and 12.1 months (95% CI 8.0-NE) in the HRd, HRp, and HRnd subgroups, respectively (June 16, 2021, cutoff). The most common any-grade treatment-related adverse events (related to niraparib and/or bevacizumab) were thrombocytopenia (74/105), fatigue (60/105), and anemia (55/105; December 24, 2020, cutoff).. Niraparib + bevacizumab first-line maintenance therapy displayed promising PFS results. Safety was consistent with the known safety profiles of niraparib and bevacizumab as monotherapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Female; Humans; Indazoles; Maintenance Chemotherapy; Ovarian Neoplasms; Piperidines; Platinum

Platinum-resistant ovarian cancer patients have a poor prognosis and few treatment options are available. Preclinical and clinical data demonstrated that the combination of poly-ADP ribose polymerase inhibitors with immune checkpoint inhibitors could have a synergistic antitumor activity in this setting of patients.. The primary objective is to assess the efficacy of niraparib plus dostarlimab compared with chemotherapy in recurrent ovarian cancer patients not suitable for platinum treatment.. This trial will assess the hypothesis that niraparib plus dostarlimab therapy is effective to increase overall survival, progression-free survival, and time to first subsequent therapy respect to chemotherapy alone, with an acceptable toxicity profile.. This is a phase III, multicenter trial, where recurrent ovarian cancer patients not eligible for platinum re-treatment will be randomized 1:1 to receive niraparib plus dostarlimab vs physician's choice chemotherapy until disease progression, intolerable toxicity, or withdrawal of patient consent. The study will be performed according to European Network for Gynaecological Oncological Trial groups (ENGOT) model B and patients will be recruited from 40 sites across MITO, CEEGOG, GINECO, HeCOG, MANGO, and NOGGO groups.. Eligible patients must have recurrent epithelial ovarian cancer not eligible for platinum retreatment. Patients who received previous treatment with poly-ADP ribose polymerase inhibitors and/or immune checkpoint inhibitors will be eligible. No more than two prior lines of treatment are allowed.. The primary endpoint is overall survival defined as the time from the randomization to the date of death by any cause.. 427 patients will be randomized.. June 2024 TRIAL REGISTRATION NUMBER: NCT04679064.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Female; Humans; Immune Checkpoint Inhibitors; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

To evaluate the efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer.. This Phase 2 open-label, single-arm study enrolled Japanese women with homologous recombination deficiency-positive relapsed, high-grade serous ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of therapy. The starting dose of niraparib was 300 mg administered once daily in continuous 28-day cycles until objective progressive disease, unacceptable toxicity, consent withdrawal or discontinuation. The primary endpoint, objective response rate (ORR), was assessed by the investigator using RECIST version 1.1. Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs), including serious TEAEs.. Twenty women were enrolled and the confirmed ORR in the full analysis set (FAS) was 35.0% (7/20), consisting of 1 complete response and 6 partial responses. Disease control rate in the FAS was 90.0%. The most frequently reported TEAEs (>50%) were anemia, nausea, and platelet count decreased. One patient (5.0%) had TEAEs leading to discontinuation of niraparib whereas reductions or interruptions were reported in 14 (70.0%) and 15 (75.0%) patients, respectively. The median dose intensity (202.9 mg daily) corresponded to a relative dose intensity of 67.6%.. Efficacy and safety of niraparib in heavily pretreated Japanese women was comparable to that seen in an equivalent population of non-Japanese women. No new safety signals were identified.. ClinicalTrials.gov Identifier: NCT03759600.

Topics: Female; Homologous Recombination; Humans; Indazoles; Japan; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

This study evaluated maintenance treatment with niraparib, a potent inhibitor of poly(ADP-ribose) polymerase 1/2, in patients with platinum-sensitive recurrent ovarian cancer.. Between 26 September 2017 and 2 February 2019, 265 patients were randomized to receive niraparib (n = 177) or placebo (n = 88); 249 patients received an ISD (300 mg, n = 14; 200 mg, n = 235) as per protocol. In the intention-to-treat population, median PFS was significantly longer for patients receiving niraparib versus placebo: 18.3 [95% confidence interval (CI), 10.9-not evaluable] versus 5.4 (95% CI, 3.7-5.7) months [hazard ratio (HR) = 0.32; 95% CI, 0.23-0.45; P < 0.0001], and a similar PFS benefit was observed in patients receiving an ISD, regardless of BRCA mutation status. Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively; the most common events were neutrophil count decreased (20.3% versus 8.0%) and anemia (14.7% versus 2.3%).. Niraparib maintenance treatment reduced the risk of disease progression or death by 68% and prolonged PFS compared to placebo in patients with platinum-sensitive recurrent ovarian cancer. Individualized niraparib dosing is effective and safe and should be considered standard practice in this setting.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; China; Double-Blind Method; Female; Humans; Indazoles; Maintenance Chemotherapy; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

The primary objective of this study was to evaluate the safety of niraparib 300 mg/day in Japanese patients with platinum-sensitive, relapsed ovarian cancer in a maintenance setting.. Phase 2, multicenter, open-label, single-arm study enrolled Japanese patients with platinum-sensitive, relapsed ovarian cancer who had received ≥2 platinum-based regimens. The primary endpoint (incidence of grade 3 or 4 thrombocytopenia-related events within 30 days after initial niraparib administration) was justified by the incidences of a global pivotal phase 3 study and its post-hoc safety analysis on thrombocytopenia, the major hematological adverse event of niraparib. The overall safety analysis examined other treatment-emergent adverse events (TEAEs).. Enrolled patients (n=19) had a median (min, max) body weight of 53.9 (40.8-79.1) kg; all but one patient weighed <77 kg. Most (94.7%) patients initially received niraparib 300 mg/day but this decreased in subsequent cycles (mean±standard deviation dose intensity, 191.6±65.7 mg/day). In total, 6/19 (31.6%) patients experienced grade 3 or 4 thrombocytopenia-related events within 30 days of initial niraparib administration. Other common TEAEs included nausea, and decreased platelet or neutrophil counts. No progression-free or overall survival events occurred; only 1 of 4 response-evaluable patients had a post-baseline tumor assessment (stable disease).. The incidence of grade 3 or 4 thrombocytopenia-related events in Japanese ovarian cancer patients was similar to that in the corresponding non-Japanese study. Overall, the safety profile was acceptable and consistent with the known safety profile and previous experience with niraparib.. ClinicalTrials.gov Identifier: NCT03759587.

Topics: Female; Humans; Indazoles; Japan; Maintenance Chemotherapy; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines

ZL-2306-005 is a randomized, double-blind, multicenter phase 3 study evaluating the efficacy and safety of niraparib, a poly(adenosine diphosphate-ribose) polymerase inhibitor, as first-line maintenance therapy in Chinese patients with platinum-responsive, extensive-stage SCLC (ES-SCLC).. Patients with complete response (CR) or partial response (PR) to standardized, platinum-based first-line chemotherapy were randomized 2:1 to receive niraparib or placebo (300 mg [baseline body weight ≥ 77 kg, platelet count ≥ 150,000/μL] or 200 mg) once daily until progression or unacceptable toxicity. Primary end points were progression-free survival (PFS) (blinded independent central review) and overall survival (sample size planned: 591 patients). Secondary end points included investigator-evaluated PFS and safety.. ZL-2306-005 was terminated early owing to ES-SCLC treatment landscape changes (data cutoff: March 20, 2020). During July 2018-February 2020, a total of 185 of 272 patients screened were randomized (niraparib: n = 125 [CR = 1, PR = 124]; placebo: n = 60 [CR = 1, PR = 59]). Median (95% confidence interval [CI]) PFS (blinded independent central review) was 1.54 months (1.41-2.69, niraparib) and 1.36 months (1.31-1.48, placebo); hazard ratio (HR) = 0.66 (95% CI: 0.46-0.95, p = 0.0242). Median overall survival was 9.92 months (9.33-13.54, niraparib) and 11.43 months (9.53-not estimable, placebo); HR = 1.03 (95% CI: 0.62-1.73, p = 0.9052). Median investigator-evaluated PFS was 1.48 months (1.41-2.56, niraparib) and 1.41 months (1.31-2.00, placebo); HR = 0.88 (95% CI: 0.61-1.26; p = 0.4653). Grade greater than or equal to 3 adverse events occurred in 34.4% (niraparib) and 25.0% (placebo) of patients.. ZL-2306-005 did not reach primary end points. Nevertheless, niraparib as maintenance therapy modestly improved PFS in patients with platinum-responsive ES-SCLC, with acceptable tolerability profile and no new safety signal.

Topics: Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Female; Humans; Indazoles; Lung Neoplasms; Maintenance Chemotherapy; Ovarian Neoplasms; Piperidines

Pharmacokinetics characteristics of niraparib in Chinese patients were similar to those in white patients. Niraparib could be well tolerated by Chinese patients, and adverse events were manageable in this study. Population pharmacokinetics analysis indicated that baseline body weight had a modest impact on pharmacokinetics parameters of niraparib; however, it was not considered clinically important.. This randomized, open-label, single-arm, phase I study was designed to investigate the pharmacokinetics (PK) and safety of niraparib in Chinese patients with epithelial ovarian cancer.. Eligible patients were randomized in a 1:1:1 ratio to receive 100, 200, or 300 mg of niraparib once daily. PK parameters were analyzed after single and multiple dose administrations.. The PK profile of niraparib in Chinese patients is consistent with that in white patients. Niraparib is safe and well tolerated in Chinese patients with ovarian cancer.

Topics: Female; Humans; Indazoles; Male; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; CD8-Positive T-Lymphocytes; DNA Mutational Analysis; Drug Monitoring; Female; Gene Amplification; Humans; Indazoles; Interferons; Macrophages; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Ovary; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Programmed Cell Death 1 Ligand 2 Protein; Programmed Cell Death 1 Receptor; Recombinational DNA Repair; Single-Cell Analysis; Treatment Outcome; Tumor Microenvironment

In China, secondary cytoreductive surgery (SCR) has been widely used in ovarian cancer (OC) over the past two decades. Although Gynecologic Oncology Group-0213 trial did not show its overall survival benefit in first relapsed patients, the questions on patient selection and effect of subsequent targeting therapy are still open. The preliminary data from our pre-SOC1 phase II study showed that selected patients with second relapse who never received SCR at recurrence may still benefit from surgery. Moreover, poly(ADP-ribose) polymerase inhibitors (PARPi) maintenance now has been a standard care for platinum sensitive relapsed OC. To our knowledge, no published or ongoing trial is trying to answer the question if patient can benefit from a potentially complete resection combined with PARPi maintenance in OC patients with secondary recurrence.. SOC-3 is a multi-center, open, randomized, controlled, phase II trial of SCR followed by chemotherapy and niraparib maintenance vs chemotherapy and niraparib maintenance in patients with platinum-sensitive second relapsed OC who never received SCR at recurrence. To guarantee surgical quality, if the sites had no experience of participating in any OC-related surgical trials, the number of recurrent lesions evaluated by central-reviewed positron emission tomography-computed tomography image shouldn't be more than 3. Eligible patients are randomly assigned in a 1:1 ratio to receive either SCR followed by 6 cycles of platinum-based chemotherapy and niraparib maintenance or 6 cycles of platinum-based chemotherapy and niraparib maintenance alone. Patients who undergo at least 4 cycles of chemotherapy and must be, in the opinion of the investigator, without disease progression, will be assigned niraparib maintenance. Major inclusion criteria are secondary relapsed OC with a platinum-free interval of no less than 6 months and a possibly complete resection. Major exclusion criteria are borderline tumors and non-epithelial ovarian malignancies, received debulking surgery at recurrence and impossible to complete resection. The sample size is 96 patients. Primary endpoint is 12-month non-progression rate.. ClinicalTrials.gov Identifier: NCT03983226.

Topics: Adolescent; China; Cytoreduction Surgical Procedures; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Positron Emission Tomography Computed Tomography; Quality of Life

Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial.. This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017).. Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured.. These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer.. ClinicalTrials.gov identifier: NCT01847274.

Topics: Carcinoma, Ovarian Epithelial; Double-Blind Method; Female; Humans; Indazoles; Maintenance Chemotherapy; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival

Platinum-based chemotherapy is the foundation of treatment for platinum-sensitive recurrent ovarian cancer, but has substantial toxicity. Bevacizumab and maintenance poly(ADP-ribose) polymerase (PARP) inhibitors both significantly improve efficacy versus standard therapy, primarily in terms of progression-free survival, and offer the potential for chemotherapy-free treatment. AVANOVA2 compared niraparib and bevacizumab versus niraparib alone as definitive treatment for platinum-sensitive recurrent ovarian cancer.. This open-label, randomised, phase 2, superiority trial in 15 university hospitals in Denmark, Sweden, Finland, Norway, and the USA enrolled women aged 18 years or older with measurable or evaluable high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, and had to have previously received platinum-containing therapy for primary disease but ≤1 prior non-platinum-containing regimen for recurrent disease. Previous treatment with bevacizumab or first-line maintenance PARP inhibitors was permitted. Eligible patients were randomly assigned 1:1 (by random permuted blocks with block sizes of two and four, no masking), stratified by homologous recombination deficiency status and chemotherapy-free interval, to receive once-daily oral niraparib 300 mg alone or with intravenous bevacizumab 15 mg/kg once every 3 weeks until disease progression. The primary endpoint was progression-free survival, assessed by the investigators in the intention-to-treat population after events in at least 62 patients. Safety was analysed in all patients who received at least one dose of study drug. This ongoing trial is registered with ClinicalTrials.gov, number NCT02354131.. Between May 23, 2016, and March 6, 2017, 97 patients were enrolled and randomly assigned: 48 to niraparib plus bevacizumab and 49 to single-agent niraparib. Median follow-up was 16·9 months (IQR 15·4-20·9). Niraparib plus bevacizumab significantly improved progression-free survival compared with niraparib alone (median progression-free survival 11·9 months [95% CI 8·5-16·7] vs 5·5 months [3·8-6·3], respectively; adjusted hazard ratio [HR] 0·35 [95% CI 0·21-0·57], p<0·0001). Grade 3 or worse adverse events occurred in 31 (65%) of 48 patients who received niraparib plus bevacizumab and 22 (45%) of 49 who received single-agent niraparib. The most common grade 3 or worse adverse events in both groups were anaemia (7 [15%] of 48 vs 9 [18%] of 49) and thrombocytopenia (5 [10%] vs 6 [12%]), and hypertension in the combination group (10 [21%] vs 0). Niraparib plus bevacizumab was associated with increased incidences of any-grade proteinuria (10 [21%] of 48 patients vs 0) and hypertension (27 [56%] of 48 vs 11 [22%] of 49) compared with niraparib alone. No treatment-related deaths occurred.. The efficacy observed with this chemotherapy-free combination of approved agents in women with platinum-sensitive recurrent ovarian cancer warrants further evaluation. A randomised phase 3 trial investigating niraparib plus bevacizumab versus chemotherapy plus bevacizumab in platinum-sensitive recurrent ovarian cancer is planned.. Nordic Society of Gynaecological Oncology and Tesaro.

Topics: Aged; Anemia, Aplastic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Endometrioid; Disease Progression; Female; Humans; Hypertension; Indazoles; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Progression-Free Survival; Proteinuria; Thrombocytopenia

Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence of. In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival.. Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred.. Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Combined Modality Therapy; Double-Blind Method; Female; Humans; Indazoles; Maintenance Chemotherapy; Middle Aged; Nausea; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Quality of Life; Survival Analysis

To analyze the safety and efficacy of niraparib in patients aged ≥70 years with recurrent ovarian cancer in the ENGOT-OV16/NOVA trial.. The trial enrolled 2 independent cohorts with histologically diagnosed recurrent ovarian, fallopian tube, or peritoneal cancer who responded to platinum rechallenge, on the basis of germline breast cancer susceptibility gene mutation (gBRCAmut) status. Patients were randomized 2:1 to receive niraparib (300 mg) or placebo once daily until disease progression. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Adverse events (AEs) of special interest were based on the known safety profile of poly(ADP-ribose) polymerase inhibitors.. Patients aged ≥70 years in the gBRCAmut cohort receiving niraparib (n = 14) had not yet reached a median PFS compared with a median PFS of 3.7 months for the same age group in the placebo arm (hazard ratio [HR], 0.09 [95% confidence interval (CI), 0.01 to 0.73]). Non-gBRCAmut patients aged ≥70 years receiving niraparib (n = 47) had a median PFS of 11.3 months compared with 3.8 months in the placebo arm (HR, 0.35 [95% CI, 0.18 to 0.71]). Median duration of follow-up in the niraparib arm was 17.3 months in patients ≥70 years and 17.2 months in patients <70 years. Frequency, severity of AEs, and dose reductions in the niraparib arm were similar in patients aged <70 and ≥ 70 years population. The most common grade ≥ 3 AEs in patients ≥70 years were hematologic: thrombocytopenia event (34.4%), anemia event (13.1%), and neutropenia event (16.4%).. For patients ≥70 years of age receiving niraparib as maintenance treatment in the ENGOT-OV16/NOVA trial, PFS benefits and incidence of any grade or serious treatment-emergent AEs were comparable to results in the younger population. Use of niraparib should be considered in this population.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Indazoles; Maintenance Chemotherapy; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Patient Reported Outcome Measures; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after third-line therapy of 5-9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy.. QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (≥18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline.. Between April 1, 2015 and Nov 1, 2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3-5) previous lines of therapy, and the median follow-up for overall survival was 12·2 months (IQR 3·7-22·1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15·6-42·6; one-sided p=0·00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 [24%] of 463 patients) and thrombocytopenia (95 [21%] of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 [7%] of 463 patients), thrombocytopenia (34 [7%] of 463 patients), and vomiting (27 [6%] of 463 patients). One death due to gastric haemorrhage was considered treatment related.. We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations.. Tesaro.

Topics: Adolescent; Adult; Aged; BRCA1 Protein; BRCA2 Protein; Canada; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Middle Aged; Mutation; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Time Factors; United States; Young Adult

In the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy.. A total of 553 patients were enrolled in the trial. Of 203 patients with a germline. Progression-free survival was improved in patients treated with niraparib compared with placebo in both the g. Patients achieved clinical benefit from maintenance treatment with niraparib regardless of response to the last platinum-based therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Female; Humans; Indazoles; Maintenance Chemotherapy; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival

Combining poly(ADP-ribose) polymerase (PARP) inhibitors with antiangiogenic agents appeared to enhance activity vs PARP inhibitors alone in a randomized phase II trial.. In AVANOVA (NCT02354131) part 1, patients with measurable/evaluable high-grade serous/endometrioid platinum-sensitive ovarian cancer received bevacizumab 15 mg/kg every 21 days with escalating doses of niraparib capsules (100, 200, or 300 mg daily) in a 3 + 3 dose-escalation design. Primary objectives were to evaluate safety and tolerability and to determine the recommended phase II dose (RP2D).. Three of 12 enrolled patients had germline BRCA2 mutations. In cycle 1, nine patients experienced grade 3 toxicities: five with hypertension, three with anemia, and one with thrombocytopenia. There was one dose-limiting toxicity (grade 4 thrombocytopenia with niraparib 300 mg), thus the RP2D was bevacizumab 15 mg/kg with niraparib 300 mg. The response rate was 50%; disease was stabilized in a further 42%. Median progression-free survival was 11.6 (95% confidence interval 8.4-20.1) months. Niraparib pharmacokinetics were consistent with historical single-agent data. Overlapping exposure was observed across the dose ranges tested on days 1 and 21.. There was one dose-limiting toxicity; other adverse events were typical PARP inhibitor and antiangiogenic class effects. Niraparib-bevacizumab showed promising activity; Part 2 (vs bevacizumab) was recently reported and phase III comparison with standard-of-care therapy is planned.

Topics: Adult; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Ovarian Epithelial; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Indazoles; Middle Aged; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival

Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo.. Since niraparib is administered orally, it is of interest to investigate the oral bioavailability (F. Six patients received an oral therapeutic dose of 300 mg niraparib, followed by a 15-min intravenous infusion of 100 µg. The F

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Area Under Curve; Biological Availability; Breast Neoplasms; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Infusions, Intravenous; Middle Aged; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Radioactive Tracers; Tandem Mass Spectrometry

Niraparib is a poly(ADP-ribose) polymerase inhibitor approved in the USA and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to treatment-emergent adverse event (TEAE) was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was carried out to identify clinical parameters that predict dose reductions.. All analyses were carried out on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (i.e., as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade ≥3 thrombocytopenia within 30 days after the first dose of niraparib and determine cut-off points for chosen variables.. Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade ≥3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150 000/µl in effect received an average daily dose ∼200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 or 100 mg was consistent with that of patients who remained at the 300 mg starting dose.. The analysis presented suggests that patients with baseline body weight of <77 kg or baseline platelets of <150 000/µl may benefit from a starting dose of 200 mg/day.. NCT01847274.

Topics: Administration, Oral; Adult; Body Weight; Dose-Response Relationship, Drug; Female; Humans; Incidence; Indazoles; Maintenance Chemotherapy; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Platelet Count; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Retrospective Studies; Risk Factors; Thrombocytopenia

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer.. In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival.. Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications.. Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274 .).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bone Marrow; Disease-Free Survival; Double-Blind Method; Female; Genes, BRCA1; Germ-Line Mutation; Homologous Recombination; Humans; Indazoles; Kaplan-Meier Estimate; Maintenance Chemotherapy; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Piperidines; Platinum Compounds; Young Adult

Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase ß-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib.. The influence of rs11623866 (c.-609G > C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel ± lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan-Meier analysis.. The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HRPFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HROS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group.. Discrepancies between preclinical success and clinical failure may be due to the patients' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response.

Topics: Adult; Aged; Alleles; Antineoplastic Agents; Carboplatin; Farnesyltranstransferase; Female; Genetic Markers; Genotype; Humans; Kaplan-Meier Estimate; Middle Aged; Ovarian Neoplasms; Paclitaxel; Piperidines; Polymorphism, Genetic; Promoter Regions, Genetic; Protein Subunits; Pyridines; Treatment Outcome; Young Adult

Vandetanib is an oral tyrosine kinase inhibitor of VEGFR-2/3, EGFR and RET, which has demonstrated clinical activity as a single agent and in combination with taxanes. We explored the efficacy, safety and toxicity of docetaxel and vandetanib in women with recurrent ovarian cancer (OC).. Women with refractory or progressive OC were randomised 1:1 to docetaxel (75 mg/m(2), IV)+vandetanib (100mg daily, PO, D+V) or docetaxel (75 mg/m(2), D). Up to three additional cytotoxic regimens for recurrence and prior anti-angiogenic agents (as primary therapy) were allowed. The primary end-point was progression free survival (PFS). The study had 84% power to detect a PFS hazard ratio of 0.65, using a one-sided P of 0.1. This corresponds to an increase in median PFS from 3.6 months to 5.6 months. Patients progressing on D were allowed to receive single agent vandetanib (D → V).. 131 Patients were enrolled; two were excluded. 16% had received prior anti-angiogenic therapy. The median PFS estimates were 3.0 mos (D+V) versus 3.5 (D); HR: 0.99 (80% CI: 0.79-1.26). 61 Patients on D+V were assessable for toxicity; 20(33%) had treatment-related Grade (G) 4 events, primarily haematologic. Similarly, 17 (27%) of 64 patients receiving D had G4 events, primarily haematologic. 27 Evaluable patients crossed-over to V. 1/27(4%) experienced a G4 event. G3 diarrhoea was observed in 4% D → V patients. Median OS was 14 mos (D+V) versus 18 mos (D → V); HR(OS): 1.25 (80% CI: 0.93-1.68). Crossover vandetanib response was 4% (1/27 evaluable patients). High plasma IL-8 levels were associated with response to D+V.. Combination docetaxel+vandetanib did not prolong PFS relative to docetaxel alone in OC patients. No unexpected safety issues were identified.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Disease-Free Survival; Docetaxel; Fallopian Tube Neoplasms; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Quinazolines; Taxoids; Treatment Outcome

Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib.. In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502.. Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8-46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19-64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7-93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer.. A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer.. Merck Sharp and Dohme.

Topics: Adult; Aged; BRCA1 Protein; BRCA2 Protein; Cohort Studies; Female; Follow-Up Studies; Heterozygote; Humans; Indazoles; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Neoplasm Recurrence, Local; Neoplasms; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Prostatic Neoplasms; Tissue Distribution

PLD is a standard treatment in patients with recurrent platinum-resistant or refractory ovarian cancer. Vandetanib is an oral once daily administered inhibitor of VEGFR-, EGFR- and RET-signaling with activity in combination with chemotherapy in some solid tumours. We aimed to establish a feasible combination therapy of PLD and vandetanib in ovarian cancer.. Eligible patients were treated with PLD 50 mg/m(2) q28 and vandetanib 100 mg/d po. It was planned to recruit at least 10 patients evaluable for toxicity over 2 treatment cycles. Primary endpoints were tolerability and safety; secondary endpoint was efficacy.. Fourteen of 15 registered patients started treatment and were evaluable for toxicity. Three patients (21%) stopped after first cycle (PD, withdrawal of consent, nausea/vomiting). The remaining 11 patients were treated for at least 2 cycles. Dose reductions of PLD and vandetanib were indicated in 4 (29%) and 5 patients (36%), respectively. The following G3/4 toxicities occurred per patient: 2 (14%) elevated liver enzymes G3, 2 (14%) neutropenia G3/4, 5 (36%) PPE G3/4, 2 (14%) mucositis G3. Tyrosine kinase inhibitor attributed side effects like hypertension or bowel perforations were not reported. Toxicity led to cessation of treatment in 4 patients (29%). Ten patients were evaluable for response: PR 1, SD 4. The median PFS was 6.7 months and median OS was 11.1 months.. The combination of PLD 50 mg/m(2)q28 and vandetanib 100 mg/d is feasible, but may be intolerable due to reported toxicity.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Female; Humans; Middle Aged; Ovarian Neoplasms; Piperidines; Polyethylene Glycols; Protein Kinase Inhibitors; Quinazolines; Skin Diseases

This study evaluates whether a molecular targeted therapy with the farnesyltransferase inhibitor lonafarnib added to standard chemotherapy in first-line treatment of advanced ovarian cancer (OC) could improve progression-free (PFS) and overall survival (OS).. We performed a prospective randomized phase II study to compare standard therapy carboplatin (C; AUC 5) and paclitaxel (T; 175 mg/m(2)) in primary advanced OC with or without lonafarnib (L). Lonafarnib was given in a dose of 100mg orally twice a day during chemotherapy and was increased afterwards to 200mg up to six months as a maintenance therapy.. 105 patients were recruited (53 patients were randomized to receive LTC, 52 to TC). Hematologic toxicity was similar in both arms. Grade 3 and 4 non-hematological toxicity, occurred significantly more often with LTC (23% versus 4%, p=0.005) and was associated with a higher dropout rate. PFS and OS were not significantly different among both arms. The LTC arm showed inferiority in the stratum with residual tumor of more than 1cm: median PFS was 11.5 months (95% CI: 7.4-14.2) compared with 16.4 (95% CI: 10.3-40.4) for TC (p=0.0141; HR=0.36 (95% CI: 0.15-0.84)) with median OS 20.6 months (95% CI: 13.1-31.0) and 43.4 months (95% CI: 15.7-) for the TC arm (p=0.012; HR=0.32 (95% CI: 0.13-0.8)).. The addition of lonafarnib did not improve PFS or OS. Patients with a residual tumor of more than 1cm had significantly shorter PFS and OS. Incorporation of lonafarnib into future studies for primary therapy of OC is not recommended.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Ovarian Epithelial; Disease-Free Survival; Female; Humans; Middle Aged; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Paclitaxel; Piperidines; Prospective Studies; Pyridines; Survival Analysis; Young Adult

Based upon promising preclinical and phase 1 trial results, combined flavopiridol and cisplatin therapy was evaluated in patients with ovarian and primary peritoneal cancers.. A two cohort phase 2 trial of cisplatin (60 mg/m2 IV) immediately followed by flavopiridol (100 mg/m2 IV, 24 h infusion; 21 day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant disease (progression>vs. ≤6 months following prior platin-based therapy). Measurable disease (RECIST)--or evaluable disease plus CA125>2X post-treatment nadir--and ECOG performance≤2 were required.. Forty-five patients were enrolled between December 23, 2004 and February 25, 2010: 40 platin-resistant (Group 1), and 5 platin-sensitive (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12). Only 10% of patients incurred grade 4 toxicities, but grade 3 toxicities were common (65%): neutropenia (17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Seven patients (17.5%) achieved a confirmed response (1 CR, 6 PR; median duration 118 days); ten additional patients (25%) attained maintained stable disease. Median time to progression was 4.3 months; overall survival was 16.1 months. Pilot translational studies assessed ascites flavopiridol level; surrogate marker studies were uninformative. In Group 2, although 4 of 5 patients responded (2 confirmed PRs with median time to progression, 10.8 months and median overall survival 20.6 months) the cohort was closed due to poor accrual.. The assessed flavopiridol and cisplatin regimen displayed clinical activity in platin resistant and sensitive ovarian/primary peritoneal cancers, meriting further study.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Survival; Cisplatin; Cohort Studies; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Flavonoids; Humans; Middle Aged; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Young Adult

To evaluate clinical activity and target modulation of vandetanib in women with recurrent ovarian cancer.. A phase II trial of orally administered vandetanib 300 mg daily was designed to include analyses of target inhibition through paired biopsies and dynamic imaging. Core 18-gauge needle biopsies and dynamic contrast-enhanced magnetic resonance imaging were obtained before initiation of therapy and 6 weeks into therapy. Biopsy samples were subjected to reverse-phase protein lysate array endpoint analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay in serially collected plasma samples.. Twelve patients entered the study, and accrual was terminated in the first stage because of lack of response or disease stabilization beyond 6 months. Adverse events included rash, diarrhea, and prolonged QT interval corrected for heart rate, but not hypertension. Exploratory analyses showed that epidermal growth factor receptor (EGFR) phosphorylation was reduced in the eight paired biopsy sets obtained; vascular endothelial growth factor (VEGF) receptor-2 phosphorylation was not consistently affected nor were dynamic contrast-enhanced MRI permeability and flow parameters. Serial plasma VEGF concentrations were variable and did not significantly change in the 11 patients assessed.. Vandetanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting. Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGF receptor-2 in ovarian tumor tissue, but only phosphorylated-EGFR was measurably inhibited by vandetanib.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Cystadenocarcinoma, Serous; Drug Administration Schedule; ErbB Receptors; Female; Humans; Middle Aged; Ovarian Neoplasms; Piperidines; Protein Kinase Inhibitors; Quinazolines; Recurrence; Signal Transduction; Treatment Failure; Vascular Endothelial Growth Factor Receptor-2

Incel (biricodar, VX-710) restores drug sensitivity to P-glycoprotein (MDR1) and multidrug-resistance-associated protein (MRP1) expressing cells. This phase II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus paclitaxel in women with advanced ovarian cancer refractory to prior paclitaxel therapy.. Eligible patients had paclitaxel-refractory disease defined as progressive disease after a minimum of two cycles of paclitaxel (weekly or 3-week schedule) or relapsed disease within 4 months of prior paclitaxel therapy. Patients received 80 mg/m(2) paclitaxel over 3 h starting 4 h after initiation of a 24-h continuous intravenous infusion of 120 mg/m(2)/h VX-710. Cycles were repeated every 3 weeks.. Fifty patients received treatment and 45 were evaluable for response. VX-710 + paclitaxel therapy was generally well tolerated. Myelosuppression was the principal toxicity, with a median Cycle 1 nadir absolute neutrophil count of 0.27 x 10(9) cells/L and a 47% overall incidence of Grade 4 neutropenia. Mild to moderate peripheral neuritis or neuropathy was the primary nonhematologic toxicity, affecting 62% of patients. Other nonhematologic toxicities were generally mild to moderate and reversible. Paclitaxel area under the concentration-versus-time curve (AUC) (16 +/- 5.3 microg x h/mL) during the first treatment cycle was comparable to standard 175 mg/m(2) paclitaxel administered over 3 h. Of the 3 patients who achieved partial responses, 2 had progressed during prior paclitaxel therapy. Twelve patients maintained stable disease and 14/45 (31%) of patients had CA-125 reductions of 50-90% for up to 24 weeks. The median time-to-disease progression was 10 weeks for the intent-to-treat population and 20.7 weeks for the CA-125 responders.. The results suggest that VX-710 with paclitaxel has modest activity in paclitaxel-resistant ovarian cancer. Further research is warranted in less heavily treated patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Female; Humans; Middle Aged; Multidrug Resistance-Associated Proteins; Neoplasm Recurrence, Local; Ovarian Neoplasms; Paclitaxel; Piperidines; Pyridines

Topics: China; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

Poly (ADP-ribose) polymerase (PARP) inhibitors are a new maintenance therapy option for patients with ovarian cancer (OC).. To evaluate the efficacy and influencing factors of the novel PARP inhibitor niraparib for maintenance treatment of Chinese patients with advanced OC.. In this retrospective multicenter real-world study patients with advanced OC from 15 hospitals throughout China were enrolled. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included the time to treatment discontinuation and safety. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to identify possible risk factors for PFS, after which a prediction model was established to evaluate the likelihood of achieving an 18-month PFS. The relationship between the dose of niraparib and PFS was also evaluated.. The PFS rates of 199 patients at 6, 12, 18, 24, and 30 months were 87.4%, 75.9%, 63.6%, 56.1%, and 51.8%, respectively. LASSO regression model revealed that only age < 65 years (P = 0.011), BRCA mutations (P < 0.001), and R0 status after cytoreductive surgery (P = 0.01) were significant factors associated with prolonged PFS times. Based on the LASSO logistic regression analysis, a clinical prediction formula was developed: - 2.412 + 1.396Age. For Chinese OC patients, niraparib, particularly at a 200 mg individual starting dose, was an effective therapy with easily manageable safety.. Maintenance therapy with poly (ADP-ribose) polymerase inhibitors is a new option for patients with ovarian cancer (OC) after they have received platinum-based chemotherapy to reduce the recurrence or relapse rates, but it remains unclear whether there are any changes in efficacy and safety when different starting doses of niraparib are administrated to Chinese patients, who typically have a bodyweight < 77 kg. We found that niraparib exhibited satisfactory efficacy with tolerable safety during maintenance therapy for advanced OC whether administered at 100 mg or 200 mg doses. We believe these regimens can serve as a valuable addition to the previous results of randomized controlled trials.

Topics: Aged; Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

Resistance to platinum and PARP inhibitors represents a major barrier to the long-term survival of ovarian cancer patients. We aim to explore the potential role of chronic stress in drug resistance in ovarian cancer. Leveraging four ovarian cancer with chronic stress (OCCS) mouse models, we explore the therapeutic efficacy of platinum, Niraparib, and Docetaxel treatment in vivo, and compare the efficacy of these anti-tumor drugs in vitro using cell viability assays. Comparing the transcriptional characteristics in RNA-Seq of OCCS mice with public databases, we analyze the molecular mechanism of chronic stress promoting drug resistance in ovarian cancer. We find that chronic stress is positively correlated with platinum-resistant recurrence in ovarian cancer patients. Chronic stress can induce platinum and Niraparib resistance of ovarian cancer, but it does not affect the therapeutic efficacy of Docetaxel treatment in vivo. And the platinum-resistant cell lines are not sensitive to these anti-tumor drugs, which is different from the result in vivo. Then, we identify several gene networks and their constituent genes that are most significantly associated with chronic stress and drug resistance in ovarian cancer, including the glycolysis pathway and DNA damage. This study develops Niraparib and platinum-resistant in vivo models, reflecting the ability of OCCS mice to reproduce different aspects of human ovarian cancer molecular mechanism, and provides a new theoretical basis for overcoming the double drug resistance of ovarian cancer.

Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Indazoles; Mice, Inbred BALB C; Mice, Inbred C57BL; Middle Aged; Models, Biological; Ovarian Neoplasms; Piperidines; Platinum; Stress, Psychological

High-grade serous ovarian cancer (HGSOC) is the most common form of ovarian cancer diagnosed in patients worldwide. Patients with

Topics: Cell Line, Tumor; Chromatography, High Pressure Liquid; Female; Humans; Indazoles; Indoles; Mass Spectrometry; Mitochondria; Neoplasm Grading; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Proteomics; Signal Transduction

Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Indoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Platinum; Poly(ADP-ribose) Polymerase Inhibitors

Topics: Carcinoma, Ovarian Epithelial; Cytoreduction Surgical Procedures; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

In a previous paper, we demonstrated the synergistic action of the anti-ischemic lubeluzole (Lube S) on the cytotoxic activity of doxorubicin (Dox) and paclitaxel in human ovarian cancer A2780 and lung cancer A549 cells. In the present paper, we extended in vitro the study to the multi-drug-resistant A2780/DX3 cell line to verify the hypothesis that the Dox and Lube S drug association may potentiate the antitumor activity of this anticancer compound also in the context of drug resistance. We also evaluated some possible mechanisms underlying this activity. We analyzed the antiproliferative activity in different cancer cell lines. Furthermore, apoptosis, Dox accumulation, MDR1 downregulation, ROS, and NO production in A2780/DX3 cells were also evaluated. Our results confirm that Lube S improves Dox antiproliferative and apoptotic activities through different mechanisms of action, all of which may contribute to the final antitumor effect. Moderate stereoselectivity was found, with Lube S significantly more effective than its enantiomer (Lube R) and the corresponding racemate (Lube S/R). Docking simulation studies on the ABCB1 Cryo-EM structure supported the hypothesis that Lube S forms a stable MDR1-Dox-Lube S complex, which hampers the protein transmembrane domain flipping and blocks the efflux of Dox from resistant A2780/DX3 cells. In conclusion, our in vitro studies reinforce our previous hypothesis for repositioning the anti-ischemic Lube S as a potentiating agent in anticancer chemotherapy.

Topics: Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Doxorubicin; Female; Humans; Ovarian Neoplasms; Piperidines

Although cisplatin is the most active drug for the treatment of ovarian cancer, majority of patients develop resistance and ultimately relapse. Enhancing the efficacy of cisplatin could represent a promising strategy to improve the clinical outcome of patients with ovarian cancer. AT7519 is a multitargeted cyclin-dependent kinase (CDK) inhibitor and displays potent anticancer activities. In this work, we show that the combination of AT7519 with cisplatin is much more superior to cisplatin alone in inhibiting ovarian cancer. AT7519 at nanomolar concentrations inhibits proliferation and migration and induces apoptosis of multiple ovarian cancer cell lines. In contrast, AT7519 at the same concentrations either does not affect survival or is significantly less effective in inhibiting proliferation and migration in normal ovarian cells and fibroblast cells. AT7519 significantly augments the inhibitory effects of cisplatin in ovarian cancer cells in a dose-dependent manner. Mechanistic studies suggest that AT7519 (i) inhibits proliferation via decreasing activities of CDK1 and 2, and via inhibiting RNA transcription; (ii) inhibits migration via suppressing epithelial-mesenchymal transition (EMT); and (iii) induces apoptosis via decreasing Mcl-1 and increasing Bim in ovarian cancer cells. Using a human ovarian cancer xenograft mouse model, we confirm the in vivo efficacy of AT7519 alone, and the synergistic effects of AT7519 and cisplatin in combination, at doses that cause minimal toxicity in mice. Our findings provide systematic preclinical evidence to support the initialization of clinical trials of the AT7519 and cisplatin combination for the treatment of ovarian cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Cyclin-Dependent Kinases; Drug Resistance, Neoplasm; Humans; Mice; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Pyrazoles; Signal Transduction

In the base case, olaparib was the more cost-effective treatment regimen. The ICERs for olaparib and niraparib compared to placebo were NT$1,804,785 and NT$2,340,265 per PFS-LY, respectively. Tornado analysis showed that PFS and the total resource use cost of niraparib regimen for patients without. Olaparib was estimated to be less cost and more effective compared to niraparib as maintenance therapy for patients with recurrent platinum-sensitive ovarian cancer.

Topics: Cost-Benefit Analysis; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines

Niraparib is effective against epithelial ovarian cancer (EOC), but with adverse effects. In this study, we retrospectively investigated niraparib maintenance treatment feasibility in Korean patients newly diagnosed with EOC.. The medical records of 35 patients were reviewed. Data on the baseline clinical characteristics were collected, and adverse effects were described.. Sixteen patients underwent treatment suspension or dose reduction. There was no significant difference in adverse effects (A/E) due to the interval between adjuvant chemotherapy conclusion and niraparib initiation. The two groups had similar International Federation of Gynaecology and Obstetrics (FIGO) stages. The number of patients with a history of bevacizumab use was higher in the dose modification group than in the standard dose group.. Niraparib use must be considered in those previously treated with bevacizumab. There is a need for prospective research on lower dose (<200 mg) treatments in patients with risk factors.

Topics: Carcinoma, Ovarian Epithelial; Chemotherapy, Adjuvant; Drug Tapering; Feasibility Studies; Female; Humans; Indazoles; Maintenance Chemotherapy; Neoplasm Staging; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Republic of Korea; Retrospective Studies; Survival Analysis; Treatment Outcome

The objective of this study was to evaluate medical adherence for patients with ovarian cancer who initiated treatment with a PARP inhibitor therapy, and to identify factors associated with nonadherence.. We used the MarketScan Database to identify ovarian cancer patients who initiated PARP inhibitor therapy between January 1, 2008 and December 31, 2017. The primary outcome was adherence defined as ≥ 80% proportion of days covered (PDC). A secondary outcome included adherence assessed using the medication possession ratio (MPR). Multivariable logistic regression analysis was performed to assess relation between PDC and explanatory variables. Sensitivity analysis was performed to evaluate impact of dose-adjustments and toxicity-related delays on adherence.. Among 170,976 patients diagnosed with ovarian cancer, 151 patients met inclusion criteria. The median time from diagnosis to initiating therapy was 33 months. Overall, 40 (26.5%) were non-adherent based on a PDC less than 80%. Non-adherent patients were more likely to receive niraparib and have a longer duration of therapy (p < 0.05). We found no significant impact of age, comorbidities, insurance plan, or year of PARP inhibitor initiation on non-adherence. In a sensitivity analysis to assess different definition of adherence, non-adherence ranged from 11.3% to 41.1%. When accounting for possible dose-adjustments, 21.2% of patients were non-adherent.. This population based study of ovarian cancer patients found that a quarter of patients may be sub-optimally adherent to PARP inhibitor therapy. Future research should focus on identification of patients at risk for nonadherence and interventions to lower nonadherence among these patients.

Topics: Female; Humans; Indazoles; Medication Adherence; Middle Aged; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Retrospective Studies

Topics: Adult; Aged; Budgets; Cost-Benefit Analysis; Female; Humans; Indazoles; Middle Aged; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; United States

Immune checkpoint blockades (ICBs) therapy showed limited efficacy in ovarian cancer management. Increasing evidence indicated that conventional and targeted therapies could affect tumor-associated immune responses and increase the effectiveness of immunotherapy. However, the effects of Niraparib, one of the poly (ADP) ribose polymerase (PARP) inhibitors, on the immune response remains unclear. Delineating the crosstalk between cytotoxic anticancer agents and cancer-associated immunity may lead to more efficient combinatorial strategies.. Programmed death ligand 1 (PD-L1) expression in human ovarian cancer cells after PARP inhibitors treatment was examined by western blotting (WB) and flow cytometry. The expression of poly ADP-ribose polymerase (PARP1), PD-L1, and CD8 in human ovarian cancer tissues was detected by immunohistochemistry(IHC). The effect of Niraparib and PD-L1 blockade in ovarian cancer progression was investigated in vivo. The changes of immune cells and cytokines in vitro and in vivo were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Changes of cGAS/STING signal pathway after Niraparib treatment were determined by WB, ELISA.. Niraparib upregulated membrane PD-L1 and total PD-L1 expression in ovarian cancer cells and had a synergistic effect with PD-L1 blockade in vivo. In clinical patient samples, Niraparib augmented cytotoxic CD8. Niraparib could modulate the immune response via the activation of the cGAS/STING pathway, and combination with PD-L1 blockade could further enhance the effect. These results provide a sound theoretical basis for clinical treatment.

Topics: B7-H1 Antigen; Female; Humans; Immunity; Indazoles; Ovarian Neoplasms; Piperidines

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but often lethal cancer that is diagnosed at a median age of 24 years. Optimal management of patients is not well defined, and current treatment remains challenging, necessitating the discovery of novel therapeutic approaches. The identification of SMARCA4-inactivating mutations invariably characterizing this type of cancer provided insights facilitating diagnostic and therapeutic measures against this disease. We show here that the BET inhibitor OTX015 acts in synergy with the MEK inhibitor cobimetinib to repress the proliferation of SCCOHT

Topics: Animals; Azetidines; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Synergism; Epigenesis, Genetic; Female; Gene Knockdown Techniques; HEK293 Cells; Humans; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Neoplasm Proteins; Nucleotides; Ovarian Neoplasms; Piperidines; Protein Kinase Inhibitors; S Phase; Xenograft Model Antitumor Assays

Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Approval; Female; Humans; Indazoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Topics: Carcinoma, Ovarian Epithelial; Fallopian Tubes; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

Poly (ADP-ribose) polymerase 1 inhibitors (PARPi) are used to treat recurrent ovarian cancer (OC) patients due to greater survival benefits and minimal side effects, especially in those patients with complete or partial response to platinum-based chemotherapy. However, acquired resistance of platinum-based chemotherapy leads to the limited efficacy of PARPi monotherapy in most patients. Twist is recognized as a possible oncogene and contributes to acquired cisplatin resistance in OC cells. In this study, we show how Twist knockdown cisplatin-resistant (CisR) OC cells blocked DNA damage response (DDR) to sensitize these cells to a concurrent treatment of cisplatin as a platinum-based chemotherapy agent and niraparib as a PARPi on in vitro two-dimensional (2D) and three-dimensional (3D) cell culture. To investigate the lethality of PARPi and cisplatin on Twist knockdown CisR OC cells, two CisR cell lines (OV90 and SKOV3) were established using step-wise dose escalation method. In addition, in vitro 3D spheroidal cell model was generated using modified hanging drop and hydrogel scaffolds techniques on poly-2-hydroxylethly methacrylate (poly-HEMA) coated plates. Twist expression was strongly correlated with the expression of DDR proteins, PARP1 and XRCC1 and overexpression of both proteins was associated with cisplatin resistance in OC cells. Moreover, combination of cisplatin (Cis) and niraparib (Nira) produced lethality on Twist-knockdown CisR OC cells, according to combination index (CI). We found that Cis alone, Nira alone, or a combination of Cis+Nira therapy increased cell death by suppressing DDR proteins in 2D monolayer cell culture. Notably, the combination of Nira and Cis was considerably effective against 3D-cultures of Twist knockdown CisR OC cells in which Endoplasmic reticulum (ER) stress is upregulated, leading to initiation of mitochondrial-mediated cell death. In addition, immunohistochemically, Cis alone, Nira alone or Cis+Nira showed lower ki-67 (cell proliferative marker) expression and higher cleaved caspase-3 (apoptotic marker) immuno-reactivity. Hence, lethality of PARPi with the combination of Cis on Twist knockdown CisR OC cells may provide an effective way to expand the therapeutic potential to overcome platinum-based chemotherapy resistance and PARPi cross resistance in OC.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Endoplasmic Reticulum Stress; Female; Humans; Indazoles; Mitochondria; Nuclear Proteins; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Signal Transduction; Synthetic Lethal Mutations; Twist-Related Protein 1

Our goal was to examine the anticancer effects of piperine against the resistant human ovarian cancer cells and to explore the molecular mechanisms responsible for its anticancer effects. Our study used drug-sensitive ovarian cancer cell line W1 and its sublines resistant to paclitaxel (PAC) and topotecan (TOP). We analyzed the cytotoxic effect of piperine and cytostatic drugs using an MTT assay. The impact of piperine on protein expression was determined by immunofluorescence and Western blot. We also examined its effect on cell proliferation and migration. We noticed a different level of piperine resistance between cell lines. Piperine increases the cytotoxic effect of PAC and TOP in drug-resistant cells. We observed an increase in PTPRK expression correlated with decreased pTYR level after piperine treatment and downregulation of P-gp and BCRP expression. We also noted a decrease in COL3A1 and TGFBI expression in investigated cell lines and increased COL3A1 expression in media from W1PR2 cells. The expression of Ki67 protein and cell proliferation rate decreased after piperine treatment. Piperine markedly inhibited W1TR cell migration. Piperine can be considered a potential anticancer agent that can increase chemotherapy effectiveness in cancer patients.

Topics: Aldehyde Dehydrogenase 1 Family; Alkaloids; Antineoplastic Agents; Benzodioxoles; Cell Line, Tumor; Cell Survival; Collagen Type III; Drug Resistance, Neoplasm; Extracellular Matrix Proteins; Female; Humans; Ovarian Neoplasms; Paclitaxel; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Retinal Dehydrogenase; Transforming Growth Factor beta

Niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for first/second-line maintenance treatment of ovarian cancer patients with complete or partial response to platinum-based chemotherapy, and multi-line monotherapy in BRCAmt patients or platinum-sensitive recurrence patients with homologous recombination deficiency (HRD). We present real-world experience from a single center of China.. Patients treated with niraparib in Jiangsu Cancer Hospital between June 2019 to July 2020 were recruited. The initial dose was given according to individualization. Response and adverse events (AEs) were analyzed by Response Evaluation Criteria in Solid Tumors v1.1. and National Cancer Institute Common Terminology Criteria for Adverse Events v5.0, respectively. HRD testing (AmoyDx®) was detected in most patients. Treatment was given until unequivocal progression or intolerable toxicity.. Twenty-two patients all received niraparib at a bolus of 200 mg/d. Fifty percent of patients with high-grade serous ovarian cancer are HRD-positive. Six patients underwent first-line maintenance therapy. Sixteen patients received exploratory therapy. Ultimately image evaluation revealed that two patients achieved partial response (PR) and one patient achieved stable disease (SD), yielding objective response rate (ORR) of 33.3% (95%CI = 0.060-0.759) and disease control rate (DCR) of 50% (95%CI = 0.140-0.861) in the exploratory multi-line monotherapy group. The most common AEs were nausea, thrombocytopenia, and anemia. Grade 3-4 thrombocytopenia were managed by dose reduction and interruption. Leg swelling was observed as a new adverse event.. It is feasible that patients receiving a bolus of 200 mg/d in patients from Chinese population can acquire promising efficacy and tolerance. This is the first real-world data about niraparib in ovarian cancer patients with available HRD status from China.

Topics: Adult; Aged; China; Female; Humans; Indazoles; Middle Aged; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors exhibit promising activity against ovarian cancers, but their efficacy can be limited by acquired drug resistance. This study explores the role of autophagy in regulating the sensitivity of ovarian cancer cells to PARP inhibitors.. Induction of autophagy was detected by punctate LC3 fluorescence staining, LC3I to LC3II conversion on Western blot analysis, and electron microscopy. Enhanced growth inhibition and apoptosis were observed when PARP inhibitors were used with hydroxychloroquine, chloroquine (CQ), or LYS05 to block the hydrolysis of proteins and lipids in autophagosomes or with small interfering RNA against ATG5 or ATG7 to prevent the formation of autophagosomes. The preclinical efficacy of the combination of CQ and olaparib was evaluated with a patient-derived xenograft (PDX) and the OVCAR8 human ovarian cancer cell line.. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) induced autophagy in a panel of ovarian cancer cells. Inhibition of autophagy with CQ enhanced the sensitivity of ovarian cancer cells to PARP inhibitors. In vivo, olaparib and CQ produced additive growth inhibition in OVCAR8 xenografts and a PDX. Olaparib inhibited PARP activity, and this led to increased reactive oxygen species (ROS) and an accumulation of γ-H2AX. Inhibition of autophagy also increased ROS and γ-H2AX and enhanced the effect of olaparib on both entities. Treatment with olaparib increased phosphorylation of ATM and PTEN while decreasing the phosphorylation of AKT and mTOR and inducing autophagy.. PARP inhibitor-induced autophagy provides an adaptive mechanism of resistance to PARP inhibitors in cancer cells with wild-type BRCA, and a combination of PARP inhibitors with CQ or other autophagy inhibitors could improve outcomes for patients with ovarian cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Chloroquine; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Indazoles; Mice, Nude; Mice, SCID; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Xenograft Model Antitumor Assays

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Platinum-based chemotherapy induces cellular senescence. Notably, therapy-induced senescence contributes to chemoresistance by inducing cancer stem-like cells (CSC). However, therapeutic approaches targeting senescence-associated CSCs remain to be explored. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT) inhibition suppresses senescence-associated CSCs induced by platinum-based chemotherapy in EOC. Clinically applicable NAMPT inhibitors suppressed the outgrowth of cisplatin-treated EOC cells both

Topics: Acrylamides; Aldehyde Dehydrogenase 1 Family; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cellular Senescence; Cisplatin; Cytokines; Drug Resistance, Neoplasm; Female; Humans; Mice; Neoplastic Stem Cells; Nicotinamide Phosphoribosyltransferase; Ovarian Neoplasms; Piperidines; Retinal Dehydrogenase; Spheroids, Cellular; Xenograft Model Antitumor Assays

Topics: Antibodies, Monoclonal, Humanized; Female; Humans; Indazoles; Mutation; Ovarian Neoplasms; Piperidines; Recombinational DNA Repair

Topics: Benzimidazoles; Clinical Trials as Topic; Female; Genes, BRCA1; Genes, BRCA2; Humans; Indazoles; Maintenance Chemotherapy; Ovarian Neoplasms; Phenotype; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

It is of current interest to target cancer metabolism as treatment for many malignancies, including ovarian cancer (OVC), in which few druggable driver mutations have been identified. Nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD salvage pathway, is a potential therapeutic target in OVC. However, factors that determine responsiveness to NAMPT inhibition are not fully understood. Here, we report that OVC cell lines can be divided into subgroups exhibiting NAMPT-dependent or NAMPT-independent glycolysis, and these metabolic differences correlate with vulnerability to NAMPT inhibition. Interestingly, cells showing NAMPT-dependent glycolysis were enriched in a group of cells lacking BRCA1/2 gene mutations. Our findings suggest the importance of selecting appropriate patients for NAMPT-targeting therapy in OVC.

Topics: Acrylamides; Cell Line, Tumor; Cytokines; Female; Glycolysis; Humans; Lactic Acid; NAD; Niacin; Nicotinamide Phosphoribosyltransferase; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease.. Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non‑platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations.. Non‑platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non‑platinum-based regimens.. High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Ovarian Epithelial; Cost-Benefit Analysis; Drug Costs; Female; Humans; Indazoles; Indoles; Infusions, Intravenous; Markov Chains; Models, Statistical; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Quality of Life; United States

Ovarian cancer is the most lethal gynecologic malignancy worldwide with poor prognosis owing to chemotherapy resistance and cancer relapse. Hence, there is an urgent need to develop novel anticancer agents against ovarian cancer.. The aim of this research is to investigate the possible anticancer activity of aloperine, an active ingredient from a traditional Chinese medicine Sophora alopecuroides, and to explore the possible Reactive Oxygen Species (ROS)-related mechanism.. Cell viability, cytotoxicity, apoptosis, ROS generation, and oxidant stress indicators were analyzed.. Our results demonstrated that aloperine significantly induced inhibition of cell viability, promoted cytotoxicity and mitochondrial-related apoptosis, and increased ROS generation in ovarian cancer cells. Furthermore, the antioxidant α-lipoic acid reversed apoptosis in aloperinetreated cells. In addition, we identified hydrogen peroxide as the main type of ROS, and the antioxidant catalase suppressed the apoptotic inducing effect of aloperine whereas hydrogen peroxide supplement exacerbated the effect of aloperine in ovarian cancer cells.. Taken together, our results indicated that aloperine could exert anti-ovarian cancer cell activity through a reactive oxygen species activation mechanism and suggested aloperine as a potential agent against ovarian cancer.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Female; Humans; Ovarian Neoplasms; Piperidines; Quinolizidines; Reactive Oxygen Species

The release of an active drug from the prodrug generates a pro-fragment that typically has no biological activity and could result in adverse effects. By combining two drugs, wherein each drug acts as a pro-fragment of the other drug will eliminate the pro-fragment in the prodrug. As they are prodrugs of each other and are symbiotic, we termed these as symbiotic prodrugs (SymProDs). To test this idea, we generated SymProDs using NFκB inhibitors that contain the reactive α-methylene-γ-butyrolactone moiety and CDK inhibitors with solvent exposed secondary nitrogen atoms. We show that secondary amine prodrugs of α-methylene-γ-butyrolactone containing NFκB inhibitors undergo slow release over a 72 hr period. Using an alkyne-tagged secondary amine prodrug of α-methylene-γ-butyrolactone containing NFκB inhibitor, we demonstrate target engagement. The NFκB-CDK SymProDs were ~20- to 200-fold less active against the corresponding CDK inhibitors in in vitro CDK kinase assays. Growth inhibition studies in a panel of ovarian cancer cell lines revealed potency trends of the SymProDs mirrored those of the single treatments suggesting their dissociation in cells. In conclusion, our results suggest that SymProDs offer a productive path forward for advancing compounds with reactive functionality and can be used as dual targeting agents.

Topics: 4-Butyrolactone; Amines; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinases; Drug Screening Assays, Antitumor; Female; Humans; Molecular Targeted Therapy; NF-kappa B; Ovarian Neoplasms; Piperazines; Piperidines; Prodrugs; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Sesquiterpenes; Signal Transduction; Structure-Activity Relationship

Topics: Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Topics: Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Female; Humans; Indazoles; Kidney Diseases; Middle Aged; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Risk Factors

Niraparib maintenance after frontline chemotherapy for advanced ovarian cancer extends progression free survival. The objective of this study was to determine the cost effectiveness of niraparib maintenance therapy in patients with newly diagnosed ovarian cancer.. Decision analysis models compared the cost of observation versus niraparib maintenance following chemotherapy for five groups: all newly diagnosed ovarian cancer patients (overall), those with homologous recombination deficiency, those harboring. For the overall group, the cost of observation was US$5.8 billion versus $20.5 billion for niraparib maintenance, with an incremental cost effectiveness ratio of $72 829. For the homologous recombination deficiency group, the observation cost was $3.0 billion versus $14.8 billion for niraparib maintenance (incremental cost effectiveness ratio $56 329). Incremental cost effectiveness ratios for the. For patients with newly diagnosed ovarian cancer, maintenance therapy with niraparib was cost effective. Cost effectiveness was improved when analyzing those patients with homologous recombination deficiency and

Topics: Carcinoma, Ovarian Epithelial; Cost-Benefit Analysis; Decision Support Techniques; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Quality-Adjusted Life Years

This study aims to describe the real-world experience, including the clinical and financial burden, associated with PARP inhibitors in a large community oncology practice.. Retrospective chart review identified patients prescribed olaparib, niraparib or rucaparib for maintenance therapy or treatment of recurrent ovarian, primary peritoneal or fallopian tube cancer across twelve gynecologic oncologists between December 2016 and November 2018. Demographic, financial and clinical data were extracted. One PARP cycle was defined as a single 28-day period. For patients treated with more than one PARPi, each course was described separately.. A total of 47 patients and 506 PARP cycles were identified (122 olaparib, 24%; 89 rucaparib, 18%; 294 niraparib, 58%). Incidence of grade ≥ 3 adverse events were similar to previously reported. Toxicity resulted in dose interruption, reduction and discontinuation in 69%, 63% and 29% respectively. Dose interruptions were most frequent for niraparib but resulted in fewer discontinuations (p-value 0.01). Mean duration of use was 7.46 cycles (olaparib 10.52, rucaparib 4.68, niraparib 7.34). Average cost of PARPi therapy was $8018 per cycle. A total of 711 phone calls were documented (call rate 1.4 calls/cycle) with the highest call volume required for care coordination, lab results and toxicity management.. Although the toxicity profile was similar to randomized clinical trials, this real-world experience demonstrated more dose modifications and discontinuations for toxicity management than previously reported. Furthermore, the clinical and financial burden of PARP inhibitors may be significant and future studies should assess the impact on patient outcomes.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Community Health Centers; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Costs; Female; Follow-Up Studies; Gynecology; Humans; Indazoles; Indoles; Medical Oncology; Medication Therapy Management; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic; Retrospective Studies; Workload

Ovarian cancer is prone to recurrence and chemotherapy resistance. Ovarian tumours of some patients have been positive for anaplastic lymphoma kinase fusion gene expression (ALK+). Preclinical studies indicate that anaplastic lymphoma kinase inhibitor can suppress the growth of ovarian cancer cells and transplantation tumours. Here, we present a patient with metastatic ALK+ high-grade serous ovarian cancer that testing positive for EML4-ALK (microtubule-associated protein-like 4 gene, fused to the anaplastic lymphoma kinase gene), experienced dramatic benefit after administration of the anaplastic lymphoma kinase inhibitor alectinib. This is the first clinical evidence that treatment with alectinib may provide a personalized maximum benefit for patients with high-grade serous ovarian cancer who are positive for EML4-ALK.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Ovarian Epithelial; Female; Humans; Middle Aged; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Ovarian Neoplasms; Piperidines; Protein Kinase Inhibitors; Treatment Outcome

Homologous recombination deficiency is a critical biologic feature of ovarian cancer. This weakness in DNA damage repair relies on functional poly(ADP-ribose) polymerase. Niraparib is a poly(ADP-ribose) polymerase inhibitor, orally available and initially approved for maintenance therapy in women with ovarian cancer by the US FDA in 2017 and by the EMA in 2017 for the same indication. Ovarian cancer represents the most lethal of gynecologic malignancies. The efficacy of niraparib has changed the landscape of ovarian cancer treatment, but overall survival data is still to come. This review summarizes the data regarding niraparib mechanism of action, toxicities, single agent efficacy and novel combinations in ovarian cancer.

Topics: Fallopian Tube Neoplasms; Female; Humans; Indazoles; Molecular Targeted Therapy; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Treatment Outcome

BACKGROUND Thrombocytopenia is a potentially treatment-limiting adverse event of particular interest with the PARP inhibitor niraparib. This adverse event may necessitate niraparib dose reduction or treatment discontinuation, resulting in suboptimal treatment outcomes. Here, we report on niraparib dose optimization in 2 patients with breast cancer and 4 patients with ovarian cancer through concurrent administration of the thrombopoietin receptor stimulating agent avatrombopag to mitigate thrombocytopenia, enabling niraparib reescalation and improved clinical response. CASE REPORT Three of 6 patients received niraparib 300 mg daily, the highest recommended dose, for a sustained period. Avatrombopag therapy enabled niraparib dose escalation that led to reductions in biomarkers associated with disease progression. Before initiation of avatrombopag, increases in CA-125 levels, a marker for ovarian cancer, were observed in association with niraparib dose interruption, and in 2 patients with ovarian cancer CA-125 levels fell in response to niraparib dose escalation enabled by concurrent avatrombopag therapy. Further, in 2 patients with metastatic breast cancer, intracranial response was observed in association with avatrombopag-enabled niraparib therapy. In 1 patient with metastatic breast cancer, niraparib induced an intracranial response, while previous use of talazoparib had not, confirming preclinical findings of superior blood-brain-barrier penetrance with niraparib. CONCLUSIONS Avatrombopag is currently approved for use in chronic immune thrombocytopenia and thrombocytopenia associated with chronic liver disease in patients undergoing a surgical procedure. A clinical trial of avatrombopag for chemotherapy-induced thrombocytopenia is ongoing. Preliminary results in these 6 patient cases demonstrate the need for a confirmatory trial of avatrombopag for optimizing the dose of niraparib.

Topics: Adenosine Diphosphate Ribose; Breast Neoplasms; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Thiazoles; Thiophenes; Thrombocytopenia

There are large randomized clinical trials-SOLO-1 (Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy [December 2018]), PRIMA (A Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy [September 2019]), and PAOLA-1 (Platine, Avastin and Olaparib in 1st Line [December 2019])-reporting positive efficacy results for maintenance regimens for women with primary, advanced epithelial ovarian cancer. The findings resulted in approval by the US Food and Drug Administration of the treatments studied as of May 2020. However, there are pressing economic considerations given the many eligible patients and substantial associated costs.. To evaluate the cost-effectiveness of maintenance strategies for patients with (1) a BRCA variant, (2) homologous recombination deficiency without a BRCA variant, or (3) homologous recombination proficiency.. In this economic evaluation of the US health care sector using simulated patients with primary epithelial ovarian cancer, 3 decision trees were developed, one for each molecular signature. The maintenance strategies evaluated were olaparib (SOLO-1), olaparib-bevacizumab (PAOLA-1), bevacizumab (PAOLA-1), and niraparib (PRIMA). Base case 1 assessed olaparib, olaparib-bevacizumab, bevacizumab, and niraparib vs observation of a patient with a BRCA variant. Base case 2 assessed olaparib-bevacizumab, bevacizumab, and niraparib vs observation in a patient with homologous recombination deficiency without a BRCA variant. Base case 3 assessed olaparib-bevacizumab, bevacizumab, and niraparib vs observation in a patient with homologous recombination proficiency. The time horizon was 24 months. Costs were estimated from Medicare claims, wholesale acquisition prices, and published sources. Probabilistic sensitivity analyses with microsimulation were then conducted to account for uncertainty and assess model stability. One-way sensitivity analyses were also performed. The study was performed from January through June 2020.. Incremental cost-effectiveness ratios (ICERs) in US dollars per progression-free life-year saved (PF-LYS).. Assuming a willingness-to-pay threshold of $100 000/PF-LYS, none of the drugs could be considered cost-effective compared with observation. In the case of a patient with a BRCA variant, olaparib was the most cost-effective (ICER, $186 777/PF-LYS). The third-party payer price per month of olaparib would need to be reduced from approximately $17 000 to $9000 to be considered cost-effective. Olaparib-bevacizumab was the most cost-effective in the case of a patient with homologous recombination deficiency without a BRCA variant (ICER, $629 347/PF-LYS), and bevacizumab was the most cost-effective in the case of patient with homologous recombination proficiency (ICER, $557 865/PF-LYS). Even at a price of $0 per month, niraparib could not be considered cost-effective as a maintenance strategy for patients with homologous recombination proficiency.. The findings of this study suggest that, at current costs, maintenance therapy for primary ovarian cancer is not cost-effective, regardless of molecular signature. For certain therapies, lowering the drug price alone may not make them cost-effective.

Topics: Antineoplastic Agents, Immunological; Bevacizumab; Carcinoma, Ovarian Epithelial; Computing Methodologies; Cost-Benefit Analysis; Female; Genes, BRCA1; Genes, BRCA2; Homologous Recombination; Humans; Indazoles; Maintenance Chemotherapy; Medicare; Neoplasm Staging; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; United States

Ovarian cancer is the second the most common gynaecological malignancy in developed countries. 70% of patients relapse in the first 3 years following debulking surgery and first-line chemotherapy. Niraparib is a poly adenosine diphosphate ribose polymerase inhibitor which uses the concept of synthetic lethality in the presence of a mutation in the breast cancer susceptibility gene (

Topics: Aged; Brain Neoplasms; Cystadenocarcinoma, Serous; Disease-Free Survival; Female; Humans; Indazoles; Maintenance Chemotherapy; Neoplasm Grading; Ovarian Neoplasms; Piperidines; Treatment Outcome

Topics: Bevacizumab; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Platinum

This study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer.. Mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline. In the g. Patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control.

Topics: BRCA1 Protein; BRCA2 Protein; Disease Progression; Drug Administration Schedule; Female; Germ-Line Mutation; Humans; Indazoles; Maintenance Chemotherapy; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors

Topics: Clinical Trials, Phase III as Topic; Drug Administration Schedule; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Randomized Controlled Trials as Topic

Topics: Bevacizumab; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Platinum

Topics: Cystadenocarcinoma, Serous; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Precision Medicine

Ovarian cancer is the second most common and the most lethal gynecological malignancy in the western world. Unfortunately, there are lack of methods for early screening and diagnosis of the disease. Because of this, most of the cases are diagnosed at an advanced stage and have poor prognosis. The standard treatment of ovarian cancer is maximal cytoreductive surgical debulking followed by platinum-based chemotherapy. There are new molecular agents available for maintenance therapy of ovarian cancer including anti-angiogenic therapies, poly adenosine diphosphate ribose polymerase inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. Niraparib is a poly adenosine diphosphate ribose polymerase inhibitor that has shown to be clinically effective as maintenance therapy in patients with platinum sensitive, recurrent ovarian cancer. Studies have shown the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of presence or absence of BRCA gene mutations or homologous recombination deficiency status. Studies have shown that treatment-emergent Grade 3 or Grade 4 hematological events were observed in patients receiving niraparib including thrombocytopenia (33.8%), anemia (25.3%) and neutropenia (19.6%). Most of the hematological laboratory abnormalities occurred within the first three treatment cycles. After dose adjustment, the incidence of hematological abnormalities was infrequent beyond cycle 3. We are reporting two cases of Grade III/IV neutropenia and thrombocytopenia in patients treated with niraparib in our institution. Unfortunately, one of the patients succumbed to septic shock secondary to right lower lobe pneumonia while severely neutropenic. The second patient's blood counts improved after discontinuing the medication and with supportive transfusions during the hospitalization.

Topics: Aged, 80 and over; Female; Hematologic Diseases; Humans; Indazoles; Middle Aged; Mutation; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

The aim was to evaluate the cost-effectiveness of niraparib compared with routine surveillance (RS), olaparib and rucaparib for the maintenance treatment of patients with recurrent ovarian cancer (OC).. A decision-analytic model estimated the cost per quality-adjusted life-year (QALY) gained for niraparib versus RS, olaparib, and rucaparib from a US payer perspective. The model considered recurrent OC patients with or without germline BRCA mutations (gBRCAmut and non-gBRCAmut), who were responsive to their last platinum-based chemotherapy regimen. Model health states were: progression-free disease, progressed disease and dead. Mean progression-free survival (PFS) was estimated using parametric survival distributions based on ENGOT-OV16/NOVA (niraparib phase III trial), ARIEL3 (rucaparib phase III trial) and Study 19 (olaparib phase II trial). Mean overall survival (OS) benefit was estimated as double the mean PFS benefit based on the relationship between PFS and OS observed in Study 19. Costs included: drug, chemotherapy, monitoring, adverse events, and terminal care. EQ-5D utilities were estimated from trial data.. Compared to RS, niraparib was associated with an incremental cost-effectiveness ratio (ICER) of US$68,287/QALY and US$108,287/QALY for gBRCAmut and non-gBRCAmut, respectively. Compared to olaparib and rucaparib, niraparib decreased costs and increased QALYs, with a cost saving of US$8799 and US$22,236 versus olaparib and US$198,708 and US$73,561 versus rucaparib for gBRCAmut and non-gBRCAmut, respectively.. Niraparib was estimated to be less costly and more effective compared to olaparib and rucaparib, and the ICER fell within an acceptable range compared to RS. Therefore, niraparib may be considered a cost-effective maintenance treatment for patients with recurrent OC.

Topics: Cost-Benefit Analysis; Decision Support Techniques; Female; Humans; Indazoles; Indoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Quality-Adjusted Life Years; Survival Rate; United States

This study aimed to evaluate the budget impact of niraparib and olaparib in patients with platinum-sensitive, recurrent ovarian cancer from a US third party payer perspective.. A budget impact model was constructed to assess the additional per member per month (PMPM) costs associated with the introduction of niraparib and olaparib, two poly ADP-ribose polymerase ribose polymerase (PARP) inhibitors recently approved to be used in platinum-sensitive, recurrent ovarian cancer patients with and without a gBRCA mutation. The model assessed both pharmacy costs and medical costs. Pharmacy costs included adjusted drug costs, coinsurance, and dispensing fees. Medical costs included costs associated with disease monitoring and management of adverse events from the treatment. Epidemiological data from the literature were used to estimate the target population size. The analysis used 1-year time frame, and patients were assumed on treatment until disease progression or death. All costs were computed in 2017 USD. One-way sensitivity analyses were conducted to evaluate the model robustness.. In a hypothetical plan of 1,000,000 members, 206 patients were estimated to be potential candidates for niraparib or olaparib maintenance treatment after applying all epidemiological parameters. At listed 30-day supply WAC prices of $14,750 for niraparib and $13,482 for olaparib, budget impacts of these two drugs were $0.169 PMPM and $0.156 PMPM, respectively, most of which were contributed by pharmacy costs. Sensitivity analyses suggested that assumptions around market share, platinum-sensitive rate after first treatment, and WAC prices affected results the most.. In this model, it was assumed that adopting niraparib and olaparib would not affect utilization of existing medications. Also, the estimated clinical parameters from clinical trials could differ from real-world data.

Topics: Antineoplastic Agents; Budgets; Female; Health Expenditures; Humans; Indazoles; Models, Econometric; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Platinum; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Survival Analysis; United States

Ovarian cancer is the leading cause of gynecologic-related mortality worldwide. Despite successful initial treatment, overall survival rates are very low because tumors develop resistance to chemotherapeutic drugs. The PI3K/mTOR pathway is a key signaling pathway involved in drug resistance of ovarian cancer cells. The aim of this study was to examine the effect of a newly developed PI3K/mTOR dual inhibitor, CMG002, on chemoresistant ovarian cancer cells.. We examined the effects of CMG002, and its synergistic effects when combined with paclitaxel or cisplatin, on cell viability, cell cycle arrest, and apoptosis of PTX-resistant SKpac17 or cisplatin-resistant A2780cis ovarian cancer cells in vitro. Western blot analysis was performed to assess expression of PI3K, p-mTOR, p-Akt, p-S6, Bim, and caspase-3. In vivo studies were carried out in a xenograft mouse model, followed by TUNEL and immunohistochemical staining of excised tumor tissue.. CMG002 showed marked toxicity against chemoresistant ovarian cancer cells and re-sensitized these cells to chemotherapeutic agents by suppressing cell proliferation and inducing G1 cell cycle arrest and apoptosis. In vivo xenograft studies revealed that treatment with CMG002, either alone or in combination with paclitaxel or cisplatin, led to a marked reduction in tumor growth. CMG002 caused marked suppression of mTOR (Ser2448), Akt (Ser473), Akt (Thr308), and S6 (Ser235/236) phosphorylation, both in vitro and in vivo.. Taken together, CMG002, a very potent PI3K/mTOR dual inhibitor, induced cytotoxicity in chemoresistant ovarian cancer cells, suggesting that this novel inhibitor might be a new therapeutic strategy for chemoresistant ovarian cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Drug Synergism; Female; G1 Phase Cell Cycle Checkpoints; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Paclitaxel; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Signal Transduction; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

PARP inhibitors have been proven clinically efficacious in platinum-responsive ovarian cancer regardless of BRCA1/2 status and in breast cancers with germline BRCA1/2 mutation. However, resistance to PARP inhibitors may preexist or evolve during treatment in many cancer types and may be overcome by combining PARP inhibitors with other therapies, such as immune checkpoint inhibitors, which confer durable responses and are rapidly becoming the standard of care for multiple tumor types. This study investigated the therapeutic potential of combining niraparib, a highly selective PARP1/2 inhibitor, with anti-PD-1 immune checkpoint inhibitors in preclinical tumor models. Our results indicate that niraparib treatment increases the activity of the type I (alpha) and type II (gamma) interferon pathways and enhances the infiltration of CD8

Topics: Animals; Antibodies; Base Sequence; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Female; Gene Expression Profiling; Humans; Immunotherapy; Indazoles; Interferons; Mice; Mice, Inbred C57BL; Mutation; Neoplasm Transplantation; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Programmed Cell Death 1 Receptor

FDA-approved treatments for platinum-sensitive recurrent ovarian cancer (PSROC) include bevacizumab and PARP inhibitors (PARPi); clinical decisions regarding therapy must be made prior to initiating chemotherapy. Using the American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) value frameworks, we assessed relative values of concurrent/maintenance biologic therapies in PSROC.. Value scores were calculated for key maintenance therapies based on randomized controlled trials: bevacizumab (OCEANS, GOG 213); olaparib (Study 19, SOLO2); niraparib (NOVA); rucaparib (ARIEL3). Personalized value scorecards were constructed for patients with germline/somatic-BRCA mutations, homologous recombination deficiency (HRD), and wild-type BRCA (wBRCA). ASCO value scores assess clinical benefit, toxicity, long-term survival, symptom palliation, treatment-free interval, and quality of life (QOL). ESMO value scores assess clinical benefit, toxicity, and QOL.. ASCO scores were highest for maintenance PARPi in germline/somatic-BRCA mutation cohorts: olaparib (SOLO2) = 47, (Study 19) = 62; niraparib = 50; rucaparib = 54. HRD cohorts had slightly lower scores: niraparib = 46; rucaparib = 37. wBRCA cohorts had the lowest scores: niraparib = 26; rucaparib = 26; and olaparib (Study 19) = 32, as did patients receiving bevacizumab (OCEANS) = 35, (GOG 213) = 26. ESMO scores demonstrated high-value for maintenance PARPi in germline/somatic-BRCA mutation cohorts and low-value for bevacizumab and PARPi in wBRCA cohorts.. The value of maintenance PARPi therapy depends heavily on BRCA status, with the highest value scores in germline/somatic-BRCA mutation cohorts. Personalized value scorecards provide a visual aid to assess the harm-benefit balance of maintenance PARPi for PSROC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Female; Genes, BRCA1; Genes, BRCA2; Germ-Line Mutation; Humans; Indazoles; Indoles; Maintenance Chemotherapy; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Organoplatinum Compounds; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Precision Medicine; Randomized Controlled Trials as Topic

Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

Topics: Cost-Benefit Analysis; Female; Humans; Indazoles; Indoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; United States

Topics: Cost-Benefit Analysis; Female; Humans; Indazoles; Indoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; United States

Topics: Cost-Benefit Analysis; Humans; Indazoles; Indoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; United States

Epithelial ovarian cancer (EOC) has one of the highest death to incidence ratios among all cancers. High grade serous ovarian carcinoma (HGSOC) is the most common and deadliest EOC histotype due to the lack of therapeutic options following debulking surgery and platinum/taxane-based chemotherapies. For recurrent chemosensitive HGSOC, poly(ADP)-ribose polymerase inhibitors (PARPi; olaparib, rucaparib, or niraparib) represent an emerging treatment strategy. While PARPi are most effective in homologous recombination DNA repair-deficient (HRD) HGSOCs, recent studies have observed a significant benefit in non-HRD HGSOCs. However, all HGSOC patients are likely to acquire resistance. Therefore, there is an urgent clinical need to understand PARPi resistance and to introduce novel combinatorial therapies to manage PARPi resistance and extend HGSOC disease-free intervals. In a panel of HGSOC cell lines, we established matched olaparib sensitive and resistant cells. Transcriptome analysis of the matched olaparib-sensitive vs -resistant cells revealed activation of the Wnt signaling pathway and consequently increased TCF transcriptional activity in PARPi-resistant cells. Forced activation of canonical Wnt signaling in several PARPi-sensitive cells via WNT3A reduced olaparib and rucaparib sensitivity. PARPi resistant cells were sensitive to inhibition of Wnt signaling using the FDA-approved compound, pyrvinium pamoate, which has been shown to promote downregulation of β-catenin. In both an HGSOC cell line and a patient-derived xenograft model, we observed that combining pyrvinium pamoate with olaparib resulted in a significant decrease in tumor burden. This study demonstrates that Wnt signaling can mediate PARPi resistance in HGSOC and provides a clinical rationale for combining PARP and Wnt inhibitors.

Topics: Animals; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Indazoles; Indoles; Mice; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Wnt Signaling Pathway

Crenolanib is a tyrosine kinase inhibitor targeting PDGFR-α, PDGFR-β and Fms related tyrosine kinase-3 (FLT3) that is currently evaluated in several clinical trials. Although platelet-derived growth factor receptor (PDGFR) signalling pathway is believed to play an important role in angiogenesis and maintenance of functional vasculature, we here demonstrate a direct angiostatic activity of crenolanib independently of PDGFR signalling.. The activity of crenolanib on cell viability, migration, sprouting, apoptosis and mitosis was assessed in endothelial cells, tumour cells and fibroblasts. Alterations in cell morphology were determined by immunofluorescence experiments. Flow-cytometry analysis and mRNA expression profiles were used to investigate cell differentiation. In vivo efficacy was investigated in human ovarian carcinoma implanted on the chicken chorioallantoic membrane (CAM).. Crenolanib was found to inhibit endothelial cell viability, migration and sprout length, and induced apoptosis independently of PDGFR expression. Treated cells  showed altered actin arrangement and nuclear aberrations. Mitosis was affected at several levels including mitosis entry and centrosome clustering. Crenolanib suppressed human ovarian carcinoma tumour growth and angiogenesis in the CAM model.. The PDGFR/FLT3 inhibitor crenolanib targets angiogenesis and inhibits tumour growth in vivo unrelated to PDGFR expression. Based on our findings, we suggest a broad mechanism of action of crenolanib.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Benzimidazoles; Cell Movement; Chickens; Female; fms-Like Tyrosine Kinase 3; Human Umbilical Vein Endothelial Cells; Humans; Mitosis Modulators; Ovarian Neoplasms; Piperidines; Receptors, Platelet-Derived Growth Factor

We tested the hypothesis that stimulation of adiponectin receptors with the synthetic agonist AdipoRon suppresses proliferation and induces apoptotic death in human high grade serous ovarian tumor cell lines and in ex vivo primary tumors, mediated by activation of 5' AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR). We determined the effect of AdipoRon on high grade serous ovarian tumor cells lines (OVCAR3, OVCAR4, A2780) and ex vivo primary tumor tissue. Western blotting analysis was performed to examine changes in activation of AMPK and mTOR signaling and flow cytometry was utilized to examine changes in cell cycle progression. Immunofluorescence of cleaved caspase-3 positive cells and flow cytometry of annexin V positive cells were used to determine changes in apoptotic response. The CyQUANT proliferation assay was used to assess cell proliferation. AdipoRon treatment increased AMPK phosphorylation (OVCAR3 P = 0.01; A2780 P = 0.02) but did not significantly alter mTOR activity. AdipoRon induced G1 cell cycle arrest in OVCAR3 (+ 12.1%, P = 0.03) and A2780 (+ 12.0%, P = 0.002) cells. OVCAR3 and OVCAR4 cells treated with AdipoRon underwent apoptosis based on cleaved caspase-3 and annexin V staining. AdipoRon treatment resulted in a dose dependent decrease in cell number versus vehicle treatment in OVCAR3 (-61.2%, P < 0.001), OVCAR4 (-79%, P < 0.001), and A2780 (-56.9%, P < 0.001). Ex vivo culture of primary tumors treated with AdipoRon resulted in an increase in apoptosis measured with cleaved caspase-3 immunohistochemistry. AdipoRon induces activation of AMPK and exhibits an anti-tumor effect in ovarian cancer cell lines and primary tumor via a mTOR-independent pathway.

Topics: AMP-Activated Protein Kinases; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Female; Humans; Mechanistic Target of Rapamycin Complex 1; Mitosis; Models, Biological; Neoplasm Grading; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; Piperidines; Receptors, Adiponectin

Niraparib is a highly selective inhibitor of PARP-1 and PARP-2 approved in the United States for maintenance treatment of adult patients with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy. In this open-label crossover study, we evaluated the effects of food on niraparib pharmacokinetics (PK) and safety.. Patients received a single 300-mg dose of niraparib either after a high-fat meal or under fasting conditions. After a 7-day PK assessment, all patients received a second 300-mg dose of niraparib under the opposite condition, followed by 7-day PK assessment. Blood samples for PK analyses were collected at baseline (on days 1 and 8) and up to 168 h post-dose. Bioequivalence between conditions was defined by the 90% confidence intervals (CIs) for area under the plasma concentration-time curve (AUC) from 0 to last measurable concentration (AUC. The high-fat meal/fasting ratios of geometric least-squares means for AUC. A high-fat meal did not impact the PK profile of niraparib, indicating that niraparib can be taken with or without food. Niraparib was safe and well-tolerated.

Topics: Adult; Aged; Area Under Curve; Dietary Fats; Drug Monitoring; Fasting; Female; Food-Drug Interactions; Humans; Indazoles; Middle Aged; Neoplasm Recurrence, Local; Outcome Assessment, Health Care; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Therapeutic Equivalency

The irreversible ERBB1/2/4 inhibitor neratinib has been shown to rapidly down-regulate the expression of ERBB1/2/4 as well as the levels of c-MET, PDGFRα and mutant RAS proteins via autophagic degradation. Neratinib interacted in an additive to synergistic fashion with the approved PARP1 inhibitor niraparib to kill ovarian cancer cells. Neratinib and niraparib caused the ATM-dependent activation of AMPK which in turn was required to cause mTOR inactivation, ULK-1 activation and ATG13 phosphorylation. The drug combination initially increased autophagosome levels followed later by autolysosome levels. Preventing autophagosome formation by expressing activated mTOR or knocking down of Beclin1, or knock down of the autolysosome protein cathepsin B, reduced drug combination lethality. The drug combination caused an endoplasmic reticulum stress response as judged by enhanced eIF2α phosphorylation that was responsible for reducing MCL-1 and BCL-XL levels and increasing ATG5 and Beclin1 expression. Knock down of BIM, but not of BAX or BAK, reduced cell killing. Expression of activated MEK1 prevented the drug combination increasing BIM expression and reduced cell killing. Downstream of the mitochondrion, drug lethality was partially reduced by knock down of AIF, but expression of dominant negative caspase 9 was not protective. Our data demonstrate that neratinib and niraparib interact to kill ovarian cancer cells through convergent DNA damage and endoplasmic reticulum stress signaling. Cell killing required the induction of autophagy and was cathepsin B and AIF -dependent, and effector caspase independent.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; Quinolines

The FDA approved niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, on March 27, 2017, for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Approval was based on data from the NOVA trial comparing niraparib with placebo in two independent cohorts, based on germline

Topics: Aged; BRCA1 Protein; BRCA2 Protein; Clinical Trials as Topic; Drug Approval; Drug-Related Side Effects and Adverse Reactions; Female; Germ-Line Mutation; Humans; Indazoles; Maintenance Chemotherapy; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Platinum; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Progression-Free Survival; Risk Assessment

Topics: Alkaloids; Anthracenes; Apoptosis; Benzodioxoles; Caspase 3; Caspase 9; Caspase Inhibitors; Cell Proliferation; Cell Survival; Female; Humans; Imidazoles; MAP Kinase Kinase 4; Oligopeptides; Ovarian Neoplasms; p38 Mitogen-Activated Protein Kinases; Piperidines; Polyunsaturated Alkamides; Pyridines; Tumor Suppressor Proteins

PARP inhibitors have transformed treatment for ovarian cancer, a cancer notable for homologous recombination (HR) deficiencies and aberrant DNA repair, especially in the high-grade serous subtype. PARP inhibitors are now approved for recurrent ovarian cancer as maintenance following response to platinum chemotherapy and

Topics: Female; Humans; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Platinum; Poly(ADP-ribose) Polymerase Inhibitors

Topics: Double-Blind Method; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Quality of Life

Poly(ADP-ribose) polymerase (PARP) proteins are used by cells in several DNA repair processes. PARP inhibition can result in preferential death of cancer cells when another mechanism for repairing DNA is defective. Two PARP inhibitors, olaparib and rucaparib, have been approved by the US Food and Drug Administration (FDA) for the treatment of recurrent, BRCA-associated ovarian cancer. More recently, these two and a third PARP inhibitor, niraparib, were approved by the FDA as maintenance therapy following platinum-based chemotherapy for recurrent ovarian cancer. This has caused a paradigm shift in disease management and a challenge for clinicians, who must decide how best to use these agents in individualized treatment. The oral formulation is attractive to patients, but adverse effects such as nausea and fatigue can impact quality of life. As clinicians become comfortable selecting PARP inhibitors and managing associated toxicities, future steps will be to investigate how to safely administer them in combination with other therapies.

Topics: Anemia; Creatinine; Drug Administration Schedule; Drug Interactions; Exanthema; Fatigue; Female; Genes, BRCA1; Genes, BRCA2; Heart Rate; Humans; Hypertension; Indazoles; Leukopenia; Mutation; Myelodysplastic Syndromes; Nasopharyngitis; Nausea; Ovarian Neoplasms; Piperidines; Pneumonia; Poly(ADP-ribose) Polymerase Inhibitors; Thrombocytopenia; Transaminases; Vomiting

The recent approval of olaparib and niraparib as maintenance therapy can significantly affect the management of ovarian cancer. Clinical benefits, however, come with trade-offs in adverse events and costs.. To evaluate the cost-effectiveness of new ovarian cancer poly-ADP ribose polymerase (PARP) inhibitor therapies, olaparib and niraparib, as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer.. A decision tree model was constructed to evaluate the costs and effectiveness of olaparib and niraparib compared with placebo from a U.S. health care sector perspective. Costs included drug costs and costs of disease monitoring and management of adverse events throughout the treatment course. Costs were estimated from RED BOOK, Medicare reimbursement rates, and the literature and reported in 2017 U.S. dollars. Clinical effectiveness was measured in progression-free survival (PFS) life-years based on clinical trial results (NCT00753545, NCT01874353, and NCT01847274). The incremental cost-effectiveness ratio (ICER) was computed by dividing the incremental cost by the incremental effectiveness.. At base case, niraparib was the more effective treatment option with slightly higher PFS, followed by olaparib. The ICERs for niraparib and olaparib compared with common baseline placebo were $235K and $287K per PFS life-year, respectively, with olaparib extended-dominated by niraparib. Both drugs were associated with lower ICERs in patients with a gBRCA mutation than in patients without a gBRCA mutation. One-way sensitivity analysis suggested that drug prices and PFS could affect ICERs significantly, but the ICERs remained above $100K per PFS life-year within the plausible ranges of all parameters. Probabilistic sensitivity analysis suggested that niraparib was associated with higher net benefits compared with placebo only when willingness-to-pay (WTP) values were above $210K per PFS life-year thresholds.. PARP inhibitors niraparib and olaparib will extend PFS in platinum-sensitive recurrent ovarian cancer patients but are also associated with high drug acquisition costs. The base case ICERs were around or above $250K per PFS life-year in this model. No formal cost-effectiveness WTP threshold for health technology assessment exists in the United States. At a reference WTP of $100K per PFS life-year, the PARP inhibitors may not be cost-effective options.. This study was unfunded. The authors have nothing to disclose.

Topics: Clinical Decision-Making; Cost-Benefit Analysis; Female; Health Care Costs; Humans; Indazoles; Models, Economic; Neoplasm Recurrence, Local; Ovarian Neoplasms; Paclitaxel; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; United States

Oral niraparib, a highly-selective, potent poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor, is approved in the USA for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. It is also under regulatory review in the EU for use in maintenance treatment in patients with platinum-sensitive, recurrent epithelial ovarian cancer who are in response to platinum-based chemotherapy. In the multinational, phase 3 NOVA trial in adult patients with platinum-sensitive, recurrent ovarian cancer, niraparib significantly prolonged median progression-free survival, irrespective of the presence or absence of a germline BRCA (gBRCA) mutation and irrespective of the presence or absence of homologous recombinant deficiency. Niraparib is also in development for use in other solid tumours, including breast and prostate cancer. This article summarizes the milestones in the development of niraparib leading to its first global approval for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

Topics: Adult; Carcinoma, Ovarian Epithelial; Double-Blind Method; Drug Approval; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Maintenance Chemotherapy; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration

Riassunto. I PARP inibitori interferiscono con la riparazione del danno nella singola elica del DNA determinando una progressione del difetto nella doppia elica. In circa il 50% delle pazienti con carcinoma dell'ovaio sieroso di alto grado sono presenti difetti nei meccanismi di ricombinazione omologa, deputati alla riparazione del danno della doppia elica del DNA. L'incapacità di riparare il danno si traduce nella morte cellulare, un processo definito "letalità sintetica". Nella famiglia dei PARP inibitori il niraparib è stato il primo a essere approvato dalla FDA nel trattamento delle pazienti con carcinoma ovarico ricorrente indipendentemente dalla presenza o assenza di mutazioni BRCA. Questo risultato è stato raggiunto grazie ai dati emersi dal trial di fase III ENGOT-OV16/NOVA, favorevoli in termini di prolungamento della sopravvivenza libera da progressione e associati a un buon profilo di tossicità. Ulteriori trial clinici sono in corso per valutare ulteriori indicazioni all'impiego di niraparib nel trattamento del carcinoma ovarico.

Topics: Antineoplastic Agents; Disease-Free Survival; DNA Breaks, Double-Stranded; DNA Repair; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Topics: Female; Humans; Indazoles; Indoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Treatment Outcome

The p21-activated kinases (PAKs) are Cdc42/Rac-activated serine-threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt, and Wnt/β-catenin cascades. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including breast, ovary, prostate, and brain cancer. PAK1 genomic amplification at 11q13 is the most common mechanism of Pak1 hyperactivation, though Pak1 mRNA and/or protein may be overexpressed in the absence of gene amplification. In previous in vitro and in vivo studies we have shown that ovarian cancer cells with amplified/overexpressed Pak1 were significantly more sensitive to pharmacologic inhibition of Pak1 compared to cells without 11q13 amplification. In the present study we examined if additional signaling pathways might be targeted in tandem with the Group I Pak inhibitor Frax-1036 in ovarian cancer cells. Using the ICCB Known Bioactives Library, we found that the cytotoxic effect of Frax-1036 was significantly higher in combination with the PKCδ inhibitor, Rottlerin, suggesting that Pak inhibitors might be combined with other agents to treat 11q13-amplified ovarian cancer.

Topics: Acetophenones; Benzopyrans; Cell Line, Tumor; Chromosomes, Human, Pair 11; Drug Synergism; Female; Humans; Ovarian Neoplasms; p21-Activated Kinases; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrimidines; Signal Transduction

Cancer cell line profiling to identify previously unrecognized kinase dependencies revealed a novel nonmutational dependency on the DNA damage response checkpoint kinase Chk1. Although Chk1 is a promising therapeutic target in p53-deficient cancers, we found that Ras-MEK signaling engages Chk1 in a subset of osteosarcoma, ovarian, and breast cancer cells to enable their survival upon DNA damage, irrespective of p53 mutation status. Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Furthermore, exogenous DNA damage promotes Chk1 dependency, and pharmacologic Chk1 inhibition combined with genotoxic chemotherapy potentiates a DNA damage response and tumor cell killing. These findings reveal a mechanism-based diagnostic strategy to identify cancer patients that may benefit from Chk1-targeted therapy.

Topics: Animals; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Checkpoint Kinase 1; Deoxycytidine; DNA Damage; Female; Gemcitabine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 3-Ring; Humans; MAP Kinase Signaling System; Mice; Osteosarcoma; Ovarian Neoplasms; Piperidines; Proto-Oncogene Proteins p21(ras); Xenograft Model Antitumor Assays

Nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the biosynthesis of intracellular NAD+. NAMPT inhibitors have potent anticancer activity in several preclinical models by depleting NAD+ and ATP levels. Recently, we demonstrated that CD73 enables the utilization of extracellular NAD+/nicotinamide mononucleotide (NMN) by converting them to Nicotinamide riboside (NR), which can cross the plasmamembrane and fuel intracellular NAD+ biosynthesis in human cells. These processes are herein confirmed to also occur in a human ovarian carcinoma cell line (OVCAR-3), by means of CD73 or NRK1 specific silencing. Next, we investigated the anti-tumor activity of the simultaneous inhibition of NAMPT (with FK866) and CD73 (with α, β-methylene adenosine 5'-diphosphate, APCP), in an in vivo human ovarian carcinoma model. Interestingly, the combined therapy was found to significantly decrease intratumor NAD+, NMN and ATP levels, compared with single treatments. In addition, the concentration of these nucleotides in ascitic exudates was more remarkably reduced in animals treated with both FK866 and APCP compared with single treatments. Importantly, tumors treated with FK866 in combination with APCP contained a statistically significant lower proportion of Ki67 positive proliferating cells and a higher percentage of necrotic area. Finally, a slight but significant increase in animal survival in response to the combined therapy, compared to the single agents, could be demonstrated. Our results indicate that the pharmacological inhibition of CD73 enzymatic activity could be considered as a means to potentiate the anti-cancer effects of NAMPT inhibitors.

Topics: 5'-Nucleotidase; Acrylamides; Adenosine Triphosphate; Animals; Cell Line, Tumor; Cytokines; Female; GPI-Linked Proteins; Humans; Mice; Mice, Nude; NAD; Niacinamide; Nicotinamide Mononucleotide; Nicotinamide Phosphoribosyltransferase; Ovarian Neoplasms; Piperidines; Pyridinium Compounds; RNA Interference; RNA, Small Interfering

The fallopian tube epithelium is one of the potential sources of high-grade serous ovarian cancer (HGSC). The use of estrogen only hormone replacement therapy increases ovarian cancer (OVCA) risk. Despite estrogen's influence in OVCA, selective estrogen receptor modulators (SERMs) typically demonstrate only a 20 % response rate. This low response could be due to a variety of factors including the loss of estrogen receptor signaling or the role of estrogen in different potential cell types of origin. The response of fallopian tube epithelium to SERMs is not known, and would be useful when determining therapeutic options for tumors arising from this cell type, such as HGSC.. Using normal murine derived oviductal epithelial cells (mouse equivalent to the fallopian tube) estrogen receptor expression was confirmed and interaction with its ligand, estradiol, triggered mRNA and protein induction of progesterone receptor (PR). The SERMs 4-hydroxytamoxifen, raloxifene and desmethylarzoxifene, functioned as estrogen receptor antagonists in oviductal cells. Cellular proliferation and migration assays suggested that estradiol does not significantly impact cellular migration and increased proliferation. Further, using RNAseq, the oviduct specific transcriptional genes targets of ER when stimulated by estradiol and 4-hydroxytamoxifen signaling were determined and validated. The RNA-seq revealed enrichment in proliferation, anti-apoptosis, calcium signaling and steroid signaling processes. Finally, the ER and PR receptor status of a panel of HGSC cell lines was investigated including Kuramochi, OVSAHO, OVKATE, OVCAR3, and OVCAR4. OVSAHO demonstrated receptor expression and response, which highlights the need for additional models of ovarian cancer that are estrogen responsive.. Overall, the fallopian tube has specific gene targets of estrogen receptor and demonstrates a tissue specific response to SERMs consistent with antagonistic action.

Topics: Animals; Antineoplastic Agents, Hormonal; Carcinoma in Situ; Cell Line, Tumor; Drug Resistance, Neoplasm; Estradiol; Estrogen Antagonists; Estrogens; Fallopian Tubes; Female; Gene Expression Regulation, Neoplastic; Genome; Humans; Mice; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; Piperidines; Raloxifene Hydrochloride; Receptors, Estrogen; Tamoxifen; Thiophenes; Transcriptome

Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo.. Massively parallel sequencing was performed on HGSOCs to identify mutations contributing to HR deficiency. HR pathway integrity was assessed using fluorescence microscopy-based RAD51 focus formation assays. Effects of niraparib (MK-4827) on treatment-naïve PDX tumor growth as monotherapy, in combination with carboplatin/paclitaxel, and as maintenance therapy were assessed by transabdominal ultrasound. Niraparib responses were correlated with changes in levels of poly(ADP-ribose), PARP1, and repair proteins by western blotting.. Five PDX models were evaluated in vivo. Tumor regressions were induced by single-agent niraparib in one of two PDX models with deleterious BRCA2 mutations and in a PDX with RAD51C promoter methylation. Diminished formation of RAD51 foci failed to predict response, but Artemis loss was associated with resistance. Niraparib generally failed to enhance responses to carboplatin/paclitaxel chemotherapy, but maintenance niraparib therapy delayed progression in a BRCA2-deficient PDX.. Mutations in HR genes are neither necessary nor sufficient to predict response to niraparib. Assessment of repair status through multiple complementary assays is needed to guide PARP inhibitor therapy, design future clinical trials and identify ovarian cancer patients most likely to benefit from PARP inhibition.

Topics: DNA-Binding Proteins; Female; Genes, BRCA2; Homologous Recombination; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Promoter Regions, Genetic

Results from a phase III trial indicate that maintenance therapy with the PARP inhibitor niraparib is more effective than placebo in slowing the progression of recurrent platinum-sensitive ovarian cancer. Improved progression-free survival was seen regardless of the presence or absence of germline BRCA mutations, or of homologous recombination deficiency; however, patients who had these mutations or defective DNA repair did better.

Topics: BRCA1 Protein; BRCA2 Protein; Clinical Trials, Phase III as Topic; Disease Progression; Female; Germ-Line Mutation; Humans; Indazoles; Maintenance Chemotherapy; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Treatment Outcome

The purpose is to investigate the effects of the sequential combination treatment of Taxol and flavopiridol on human ovarian carcinoma in vitro and in vivo.. Cell viabilities were determined using the cell counting kit and by flow cytometry. RT-PCR, TUNEL, and immunoblotting assays were used to detect cellular apoptotic activities following treatments. Tumor growth and microvessel density (MVD) detection of mice bearing SKOV3 cells were studied.. Taxol or flavopiridol alone was cytotoxic against SKOV3 cells in vitro with a viability rate of 38.2 ± 1.3 % for 1 µmol/L Taxol and 44.3 ± 5.9 % for 300 nM flavopiridol. Sequential combination treatment with Taxol and flavopiridol resulted in a viability rate of 9.1 ± 0.8 %. The apoptotic rate of SKOV3 cells was 15.7 ± 1.7, 9.4 ± 0.4 and 51.1 ± 2.5 % for Taxol, flavopiridol, and combination of Taxol and flavopiridol, respectively. Significant synergisms were observed in SKOV3 cells in vitro, following the sequential combination of Taxol for 24 h followed by flavopiridol for 24 h, which resulted in the most substantial cell death and the highest apoptotic rate. All treatments showed significant suppression of tumor growth at the end point of the in vivo study. All treatments significantly reduce the value of MVD.. Sequential combination treatment with Taxol and flavopiridol exerted synergistic cytotoxic activities against SKOV3 cells in vitro and significantly suppress the tumor growth of mice bearing SKOV3 cells. It should be further explored as a potential clinically useful regimen against ovarian cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Drug Synergism; Female; Flavonoids; Humans; In Situ Nick-End Labeling; Mice; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Paclitaxel; Piperidines; Xenograft Model Antitumor Assays

The development of multidrug resistance (MDR) remains the significant clinical challenge in ovarian cancer therapy; however, relatively little is known about how to prevent the emergence of MDR during chemotherapy treatment. NSC23925 previously has been shown to prevent the development of MDR in osteosarcoma cells in vitro. The purpose of this study was to evaluate the effects of NSC23925 on the prevention of MDR in ovarian cancer, especially in vivo.. Human ovarian cancer cells were treated with paclitaxel alone or in combination with NSC23925 in vitro and in vivo. MDR ovarian cancer cells were established both in cultured cells and mouse models. The expression levels of Pgp and MDR1 were evaluated in various selected cell sublines by Western blot and real-time PCR. Pgp activity was also determined.. Paclitaxel treated cells eventually developed MDR with overexpression of Pgp and MDR1, and with high activity of Pgp, while paclitaxel-NSC23925 co-treated cells remained sensitive to chemotherapeutic agents in both in vitro and in vivo models. There was no observed increase in expression level and activity of Pgp in paclitaxel-NSC23925 co-treated cells. Additionally, there were no changes in the sensitivity to chemotherapeutic agents, nor expression of Pgp, in cells cultured with NSC23925.. Our findings suggest that NSC23925 can prevent the emergence of MDR in ovarian cancer both in vitro and in vivo. The clinical use of NSC2395 at the onset of chemotherapy may prevent the development of MDR and improve the clinical outcome of patients with ovarian cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Paclitaxel; Piperidines; Quinolines; Xenograft Model Antitumor Assays

Strategies to prevent the emergence of drug resistance will increase the effectiveness of chemotherapy treatment and prolong survival of women with ovarian cancer. The aim of our study is to determine the effects of NSC23925 on preventing the development of paclitaxel resistance in ovarian cancer both in cultured cells in vitro and in mouse xenograft models in vivo, and to further elucidate these underlying mechanisms. We first developed a paclitaxel-resistant ovarian cancer cell line, and demonstrated that NSC23925 could prevent the introduction of paclitaxel resistance by specifically inhibiting the overexpression of P-glycoprotein (Pgp) in vitro. The paclitaxel-resistant ovarian cancer cells were then established in a mouse model by continuous paclitaxel treatment in combination with or without NSC23925 administration in the mice. The majority of mice continuously treated with paclitaxel alone eventually developed paclitaxel resistance with overexpression of Pgp and antiapoptotic proteins, whereas mice remained sensitivity to paclitaxel and displayed lower expression levels of Pgp and antiapoptotic proteins after administered continuously with combination of paclitaxel-NSC23925. Paclitaxel-NSC23925-treated mice experienced significantly longer overall survival time than paclitaxel-treated mice. Furthermore, the combination of paclitaxel and NSC23925 therapy did not induce obvious toxicity as measured by mice body weight changes, blood cell counts and histology of internal organs. Collectively, our observations provide evidence that NSC23925 in combination with paclitaxel may prevent the onset of Pgp or antiapoptotic-mediated paclitaxel resistance, and improve the long-term clinical outcome in patients with ovarian cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Female; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Paclitaxel; Piperidines; Quinolines; Treatment Outcome; Xenograft Model Antitumor Assays

According to a Prognoscan database, upregulation of Bruton's tyrosine kinase (Btk) is associated with low overall survival in ovarian cancer patients. We found that spheroids-forming ovarian cancer cell, which highly expressed cancer stem-like cell (CSC) markers and Btk, were cisplatin resistant. We next treated CSCs and non-CSCs by a combination of ibrutinib and cisplatin. We found that chemoresistance was dependent on Btk and JAK2/STAT3, which maintained CSC by inducing Sox-2 and prosurvival genes. We suggest that addition of ibrutinib to cisplatin may improve treatment outcome in ovarian cancer.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Cisplatin; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Humans; Janus Kinase 2; Middle Aged; Neoplastic Stem Cells; Ovarian Neoplasms; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; STAT3 Transcription Factor; Young Adult

Induction of cell apoptosis and regulation of cell cycle are very attractive for treatments of tumors including ovarian carcinoma. Flavopiridol is a potent small molecular cyclin-dependent kinase(cdk) inhibitor, but its antitumor efficacy is not satisfied yet. Caspase-3 play a major role in the transduction of apoptotic signals and the execution of apoptosis in mammalian cells. We have successfully constructed the recombinant adenovirues AdHTVP2G5-rev-casp3 containing autocatalytic caspase-3 (rev-caspase-3) driven by amplified hTERT promoter system (TSTA-hTERTp). In this study, we applied it with flavopiridol to investigate their antitumor effect on ovarian cancer in vitro and in vivo.. Cell viabilities were determined using Cell Counting Kit 8 and flow cytometry. RT-PCR and immunoblotting assays were used to detect cellular apoptotic activities. Tumor growth and survival of mice bearing tumors were studied.. Flavopiridol or AdHTVP2G5-rev-casp3 at low dosage alone was mildly cytotoxic in vitro with a viability rate of 86.5 ± 4.7% for 300 nM flavopiridol and 88.9 ± 5.4% for AdHTVP2G5-rev-casp3 (MOI 20). By contrast, significant synergism of their sequential combination was observed, and the treatment of AdHTVP2G5-rev-casp3 (MOI 20) infection for 72 h, followed by flavopiridol (300 nM) for 48 h, can result in the most synergistic cell death, with cell survival rate and apoptotic rate of 11.6% and 69.7%, respectively. The sequential combination showed synergistic tumor suppression rate of 77.8%, which was significantly higher than that of AdHTVP2G5-rev-casp3 (33.6%) or flavopiridol (40.1%) alone. The mean survival of mice treated with the combination was 286 ± 8 d, which was synergistically longer than that of mice treated with AdHTVP2G5-rev-casp3 (141 ± 14d), flavopiridol (134 ± 10 d) or controls (106 ± 11 d) (P < 0.01).. The sequential combination of rev-caspase-3 and flavopiridol result in significant synergistic cell killing effects, significant tumor growth suppression and extended survival of mice bearing OVCAR3 cells. The combination should be further explored as a potential clinically useful regimen against ovarian cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Survival; Combined Modality Therapy; Female; Flavonoids; Genetic Therapy; Humans; Injections, Intraperitoneal; Mice, Nude; Ovarian Neoplasms; Piperidines; Telomerase; Tumor Burden; Xenograft Model Antitumor Assays

Lubeluzole, a neuroprotective anti-ischemic drug, and its enantiomer were prepared following a convenient procedure based on hydrolytic kinetic resolution. The ee values were >99% and 96%, respectively, as assessed by HPLC analysis. The chemosensitizing effects of both enantiomers were evaluated in combination with either doxorubicin (human ovarian adenocarcinoma A2780 cells) or paclitaxel (human lung carcinoma A549 cells) by the MTT assay. At the lowest concentrations used, lubeluzole showed an overall and remarkable tendency to synergize with both anticancer drugs. In ovarian cancer cells a clear prevalence of antagonistic effect was observed for the R-enantiomer. The synergistic effects of lubeluzole for both drugs were observed over a wide concentration window (0.005-5 μM), the lowest limit being at least 40 times lower than human plasma concentrations previously reported as causing serious side effects.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Doxorubicin; Drug Synergism; Female; Humans; Lung Neoplasms; Ovarian Neoplasms; Paclitaxel; Piperidines; Stereoisomerism; Thiazoles

Failure of platinum chemotherapy is an unresolved issue in ovarian cancer. Targeted therapy has been added to the treatment options in solid cancers. Alvocidib is a cyclin dependent kinase inhibitor.. This study evaluated the effects of alvocidib together with carboplatin on ovarian cancer cells (BG-1 and Skov-3) in vitro applying proliferation assays, cell cycle distribution analyses, apoptosis induction assays, and drug accumulation assay.. Proliferation of both cell lines was inhibited by carboplatin and alvocidib. The interaction index revealed drug synergism at distinct drug concentrations. Cell cycle distribution was altered. Alvocidib induced apoptosis in Skov-3 cells, and necrosis in BG-1 cells. Rhodamine accumulation was increased by alvocidib or both compounds together.. These data provide evidence for antiproliferative effects of alvocidib on human ovarian cancer cells in vitro associated with changes in cell cycle distribution, the induction of apoptosis, and modulation of intracellular drug accumulation. Alvocidib and carboplatin showed some cooperative activity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carboplatin; Cell Division; Cell Line, Tumor; Drug Synergism; Female; Flavonoids; Humans; Ovarian Neoplasms; Piperidines

Ovarian cancer mortality ranks highest among all gynecologic cancers with growth factor pathways playing an integral role in tumorigenesis, metastatic dissemination, and therapeutic resistance. The HER and VEGF receptor (VEGFR) are both overexpressed and/or aberrantly activated in subsets of ovarian tumors. While agents targeting either the HER or VEGF pathways alone have been investigated, the impact of these agents have not led to overall survival benefit in ovarian cancer. We tested the hypothesis that cotargeting HER and VEGFR would maximize antitumor efficacy at tolerable doses. To this end, ovarian cancer xenografts grown intraperitoneally in athymic nude mice were tested in response to AC480 (pan-HER inhibitor, "HERi"), cediranib (pan-VEGFR inhibitor "VEGFRi"), or BMS-690514 (combined HER/VEGFR inhibitor "EVRi"). EVRi was superior to both HERi and VEGFRi in terms of tumor growth, final tumor weight, and progression-free survival. Correlative tumor studies employing phosphoproteomic antibody arrays revealed distinct agent-specific alterations, with EVRi inducing the greatest overall effect on growth factor signaling. These data suggest that simultaneous inhibition of HER and VEGFR may benefit select subsets of ovarian cancer tumors. To this end, we derived a novel HER/VEGF signature that correlated with poor overall survival in high-grade, late stage, serous ovarian cancer patient tumors.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cluster Analysis; Disease Models, Animal; Disease Progression; Female; Humans; Mice; Neoplasm Grading; Ovarian Neoplasms; Piperidines; Protein Kinase Inhibitors; Proteomics; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Triazines; Tumor Burden; Xenograft Model Antitumor Assays

APO866 is a new anti-tumor compound inhibiting nicotinamide phosphoribosyltransferase (NAMPT). APO866 has an anti-tumor effect in several pre-clinical tumor models and is currently in several clinical phase II studies. 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) is a tracer used to assess cell proliferation in vivo. The aim of this study was non-invasively to study effect of APO866 treatment on [18F]FLT and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake.. In vivo uptake of [18F]FLT and [18F]FDG in human ovary cancer xenografts in mice (A2780) was studied at various time points after APO866 treatment. Baseline [18F]FLT or [18F]FDG scans were made before treatment and repeated after 24 hours, 48 hours and 7 days. Tumor volume was followed with computed tomography (CT). Tracer uptake was quantified using small animal PET/CT. One hour after iv injection of tracer, static PET scans were performed. Imaging results were compared with Ki67 immunohistochemistry.. Tumors treated with APO866 had volumes that were 114% (24 h), 128% (48 h) and 130% (Day 7) relative to baseline volumes at Day 0. In the control group tumor volumes were 118% (24 h), 145% (48 h) and 339% (Day 7) relative to baseline volumes Day 0. Tumor volume between the treatment and control group was significantly different at Day 7 (P = 0.001). Compared to baseline, [18F]FLT SUVmax was significantly different at 24 h (P<0.001), 48 h (P<0.001) and Day 7 (P<0.001) in the APO866 group. Compared to baseline, [18F]FDG SUVmax was significantly different at Day 7 (P = 0.005) in the APO866 group.. APO866 treatment caused a significant decrease in [18F]FLT uptake 24 and 48 hours after treatment initiation. The early reductions in tumor cell proliferation preceded decrease in tumor volume. The results show the possibility to use [18F]FLT and [18F]FDG to image treatment effect early following treatment with APO866 in future clinical studies.

Topics: Acrylamides; Animals; Antineoplastic Agents; Biological Transport; Cell Proliferation; Clinical Trials, Phase II as Topic; Dideoxynucleosides; Drug Monitoring; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Gene Expression; Humans; Ki-67 Antigen; Mice; Mice, Nude; Nicotinamide Phosphoribosyltransferase; Ovarian Neoplasms; Piperidines; Positron-Emission Tomography; Radiography; Radiopharmaceuticals; Tumor Burden; Xenograft Model Antitumor Assays

P-glycoprotein belongs to the ATP binding cassette transporters, responsible for the multidrug resistance of cancer cells. These transporters efflux hydrophobic drugs outside cells and decrease their therapeutic efficacy. The aim of this study was to investigate the effect of vandetanib, an oral tyrosine kinase inhibitor of EGFR, VEGFR 2 and RET kinases, on the functionality of P-gp after a 24h-treatment at therapeutic concentration (2μM), and its ability to increase the cytotoxicity of chemotherapeutic agents in multidrug resistance cancer cells. In this study we found that IGROV1-DXR and IGROV1-CDDP cells were resistant to doxorubicin and cisplatin respectively, compare to parental cell line IGROV1. The parental sensitive and the two resistant cell lines similarly expressed MRP1 and did not express BCRP. Moreover, in contrast to the IGROV1 and IGROV1-CDDP cells, IGROV1-DXR cell line overexpressed P-gp. Functional activity studies demonstrated that MRP1 was not functional and the MDR phenotype in IGROV1-DXR cells was linked to P-gp functionality. Results also showed that vandetanib reversed resistance to doxorubicin in IGROV1-DXR cells, but not to cisplatin in IGROV1-CDDP cells. After 24h of treatment, vandetanib increased the accumulation of rhodamine 123 and calcein AM, demonstrating a functional inhibition of the transporter. In IGROV1-DXR cell line, vandetanib reverse resistance to doxorubicin by inhibiting the functionality of P-gp. In conclusion, vandetanib should be an option for drug combination in patients already developing a P-gp mediated multidrug resistance.

Topics: Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Female; Fluoresceins; Fluorescent Dyes; Humans; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Ovarian Neoplasms; Phenotype; Piperidines; Protein Kinase Inhibitors; Quinazolines; Rhodamine 123; Time Factors

The synthesis of the adamantane phenylalkylamines 2a-d, 3a-c, and 4a-e is described. These compounds exhibited significant antiproliferative activity, in vitro, against eight cancer cell lines tested. The σ(1), σ(2), and sodium channel binding affinities of compounds 2a, 3a, 4a, and 4c-e were investigated. The most interesting analogue, 4a, exhibited significant in vivo anticancer profile on pancreas, prostate, leukemia, and ovarian cancer cell line xenografts together with apoptosis and caspase-3 activation. Inhibition of the cancer cells cycle at the sub-G1 level was also obtained with 4a. Finally, encouraging results were observed with 4a in vivo on mice, suggesting putative antimetastatic and analgesic activities of this compound.

Topics: Adamantane; Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Cycle; Cell Proliferation; Female; Humans; Male; Mice; Mice, SCID; Molecular Structure; Neuralgia; Ovarian Neoplasms; Pancreatic Neoplasms; Piperidines; Prostatic Neoplasms; Protein Binding; Receptors, sigma; Structure-Activity Relationship; Tumor Cells, Cultured

Topics: Adenocarcinoma; Analgesics, Opioid; Anesthesia, Local; Female; High-Intensity Focused Ultrasound Ablation; Humans; Middle Aged; Ovarian Neoplasms; Piperidines; Remifentanil

Recently, the orphan receptor G protein-coupled receptor 55 (GPR55) has been proposed as a potential cannabinoid receptor, although controversy remains on its physiological roles. Current evidence suggests a role for GPR55 as a receptor for the lysophospholipid lysophosphatidylinositol (LPI). In this study, we show that GPR55 is expressed in several prostate and ovarian cancer cell lines, both at the mRNA and at the protein level, and that it has a critical role in regulating proliferation and anchorage-independent growth. We further show that GPR55 mediates the effects of LPI in prostate and ovarian cancer cells. Indeed we demonstrate that LPI is able to induce calcium mobilization and activation of Akt and extracellular signal-regulated kinase (ERK)1/2 in these cells and that both pharmacological blockade of GPR55 and its downregulation using specific small interfering RNA strongly inhibits these processes. We further identify an autocrine loop by which LPI is synthesized by cytosolic phospholipase A2, pumped out of the cell by the ATP-binding cassette transporter ABCC1/MRP1, and is then able to initialize cascades downstream of GPR55. All together, these data demonstrate a role of LPI and its receptor GPR55 in cancer cells in activating an autocrine loop that regulates cell proliferation. These findings may have important implications for LPI as a novel cancer biomarker and for its receptor GPR55 as a potential therapeutic target.

Topics: Autocrine Communication; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Lysophospholipids; Male; Multidrug Resistance-Associated Proteins; Ovarian Neoplasms; Phospholipases A2; Piperidines; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Pyrazoles; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Rimonabant; RNA, Small Interfering

Environmental chemicals with estrogenic activity, known as xenoestrogens, may cause impaired reproductive development and endocrine-related cancers in humans by disrupting endocrine functions. Aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) is believed to play important roles in a variety of physiological processes, including estrogen signaling pathways, that may be involved in the pathogenesis and therapeutic responses of endocrine-related cancers. However, much of the underlying mechanism remains unknown. In this study, we investigated whether ARNT2 expression is regulated by a range of representative xenoestrogens in human cancer cell lines. Bisphenol A (BPA), benzyl butyl phthalate (BBP), and 1,1,1-trichloro-2,2-bis(2-chlorophenyl-4-chlorophenyl)ethane (o,p'-DDT) were found to be estrogenic toward BG1Luc4E2 cells by an E-CALUX bioassay. ARNT2 expression was downregulated by BPA, BBP, and o,p'-DDT in a dose-dependent manner in estrogen receptor 1 (ESR1)-positive MCF-7 and BG1Luc4E2 cells, but not in estrogen receptor-negative LNCaP cells. The reduction in ARNT2 expression in cells treated with the xenoestrogens was fully recovered by the addition of a specific ESR1 antagonist, MPP. In conclusion, we have shown for the first time that ARNT2 expression is modulated by xenoestrogens by an ESR1-dependent mechanism in MCF-7 breast cancer cells.

Topics: Aryl Hydrocarbon Receptor Nuclear Translocator; Basic Helix-Loop-Helix Transcription Factors; Benzhydryl Compounds; Breast Neoplasms; Cell Line, Tumor; DDT; Down-Regulation; Endocrine Disruptors; Estrogen Receptor alpha; Estrogens, Non-Steroidal; Female; Genes, Reporter; Humans; Neoplasm Proteins; Osmolar Concentration; Ovarian Neoplasms; Phenols; Phthalic Acids; Piperidines; Pyrazoles; Response Elements; RNA, Messenger; Xenobiotics

Rohitukine, a chromane alkaloid, is a precursor of flavopiridol, a promising anti-cancer compound. Currently in Phase III clinical trials, flavopiridol is a potent inhibitor of several cyclin-dependent kinases (CDKs). Rohitukine was first reported from Amoora rohituka (0.083% dry weight) followed by that in Dysoxylum binectariferum (0.9% dry weight), both belonging to the family Meliaceae. Here, we report incredibly high yields of rohitukine (7% dry weight) in trees of D. binectariferum from the Western Ghats, India. Crude extracts of the tree were found to be highly effective against ovarian and breast cancer lines tested.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Female; Flavonoids; Humans; India; Limonins; Meliaceae; Neoplasms; Ovarian Neoplasms; Phytotherapy; Piperidines; Plant Bark; Plant Extracts; Plant Stems; Protein Kinase Inhibitors; Trees

Aminopeptidase N (APN/CD13) is an essential peptidase involved in the process of tumor growth, metastasis and angiogenesis. Inhibition of APN/CD13 may be an effective strategy for cancer treatment. CIP-13F is a cyclic-imide peptidomimetics compound designed to fit the active pockets S1 and S'1 of APN/CD13 that act in tumor proliferation. Our aim in this study was to evaluate the efficacy of CIP-13F as a candidate compound for cancer treatment. The experiments were performed on the human ovarian carcinoma (OVCA) ES-2 and HRA cell lines, which have high and low levels of APN/CD13 respectively. CIP-13F significantly blocked APN/CD13 activity on the surface of ES-2 cells as measured by quantitating the enzymatic cleavage of the substrate l-leucine-p-nitroanilide. CIP-13F effectively inhibited ES-2 cell growth and migration without significant cytotoxic effect. In contrast, CIP-13F did not significantly inhibit HRA cell growth, indicating that CIP-13F may inhibit ES-2 cell growth via suppression of APN/CD13. The suppression of APN/CD13 was also observed by using the assays of flow cytometry and Western blot analysis. Further, the inhibitory effects of CIP-13F on APN/CD13 and on ES-2 proliferation were supported by the induction of ES-2 apoptosis. CIP-13F-treated ES-2 cells resulted apoptotic characteristics, such as induction of externalization of phosphatidylserine and DNA laddering fragment. The activation of caspase-3 and poly ADP-ribose polymerase (PARP) was also enhanced. The inhibitory effects of CIP-13F on APN/CD13 expression and on ES-2 proliferation were confirmed in mice bearing ES-2 xenografts. CIP-13F delayed the growth of ES-2 xenografts in mice after 2 weeks of vena caudalis injection. These results suggest that CIP-13F has a high inhibitory effect on the growth of OVCA cells via decreasing the activity and expression of APN/CD13.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; CD13 Antigens; Cell Division; Cell Line, Tumor; Female; Flow Cytometry; Humans; Imides; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Molecular; Molecular Mimicry; Ovarian Neoplasms; Peptides, Cyclic; Piperidines; Protease Inhibitors

Deregulated expression of the hepatocyte growth factor (HGF) receptor, c-Met, in cancer contributes to tumor progression and metastasis. The objective of this study was to determine whether blocking c-Met with an orally available c-Met inhibitor, PF-2341066, reduces tumor burden and increases survival in a xenograft model of ovarian cancer metastasis. Treatment of mice injected interperitoneally with SKOV3ip1 cells showed reduced overall tumor burden. Tumor weight and the number of metastases were reduced by 55% (P < .0005) and 62% (P < .0001), respectively. Treatment also increased median survival from 45 to 62 days (P = .0003). In vitro, PF-2341066 reduced HGF-stimulated phosphorylation of c-Met in the tyrosine kinase domain as well as phosphorylation of the downstream signaling effectors, Akt and Erk. It was apparent that inhibition of the pathways was functionally important because HGF-induced branching morphogenesis was also inhibited. In addition, proliferation and adhesion to various extracellular matrices were inhibited by treatment with PF-2341066, and the activity of matrix metalloproteinases was decreased in tumor tissue from treated mice compared with those receiving vehicle. Overall, these data indicate that PF-2341066 effectively reduces tumor burden in an in vivo model of ovarian cancer metastasis and may be a good therapeutic candidate in the treatment of patients with ovarian cancer.

Topics: Animals; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Crizotinib; Female; Hepatocyte Growth Factor; Humans; Immunohistochemistry; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasm Metastasis; Ovarian Neoplasms; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Signal Transduction; Survival Analysis; Tumor Burden; Xenograft Model Antitumor Assays

A new piperidine alkaloid and three known tetranortriterpenoids were isolated from the methanol extracts of the rhizomes of Arisaema decipiens Schott (Araceae) and their chemical structures were identified as (-)-(2R*,3S*,6S*)-N,2-dimethyl-3-hydroxy-6-(9-phenylnonyl) piperidine (1), 6-deacetylnimbin (2), 28-deoxonimbolide (3) and nimbin (4). The N-methylated derivative (1a) of 1 was synthesized. Compound 1 exhibited weak inhibitory activity against the MCF-7 cell line, while compound 1a showed potential inhibitory activity against the MCF-7 cell line with an IC₅₀ value of 4.6 μM and weak inhibitory activity against K562 and SK-OV-3 cells. This plant in genus Arisaema is firstly reported as the source of limonoids that are considered a natural antitumor herbal medicine.

Topics: Alkaloids; Antineoplastic Agents; Arisaema; Breast Neoplasms; Cell Line, Tumor; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Ethnicity; Female; Humans; Limonins; Magnetic Resonance Imaging; Ovarian Neoplasms; Piperidines; Rhizome

to investigate the antitumor effects on ovarian cancer using recombinant adenoviruses expressing autocatalytic caspase-3 driven by amplified human telomerase reverse transcriptase promoter (AdHTVP2G5-rev-casp3) combined with flavopiridol.. following the treatment with AdHTVP2G5-rev-casp3 combined with flavopiridol, cell survival rate was measured by cell counting kit 8; cell apoptotic rate and cell cycle distribution were detected by flow cytometry. Western blot was performed to observe the expression of p17, the active subunit of caspase-3, and p85, the cleavage segment of substrate of caspase-3, in AO cells. The mice survival rates were measured for abdominally metastatic tumor models and the volume of tumor nodules were determined for subcutaneous tumor models following the treatments of AdHTVP2G5-rev-casp3 combined with flavopiridol. HE staining was used to detect the histopathological changes of various organs, and the serum level of alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured to monitor liver damages following the intraperitoneal administration of AdHTVP2G5-rev-casp3 and flavopiridol.. there was no significant cell-killing effects or apoptosis in AO cells following treatments with AdHTVP2G5-rev-casp3 or flavopiridol at low dosage alone (apoptotic rate all < 11%), whereas significant synergism of their sequential combination was observed in AO cells. This sequential treatment of AdHTVP2G5-rev-casp3 [multiplicity of infection (MOI) was 20] infection for 72 hours, followed by flavopiridol (300 nmol/L) for 48 hours, could result in the most substantial cell death, and AO cells survival rate and apoptotic rate were 73.5% and 11.6%, respectively. Following treatments with AdHTVP2G5-rev-casp3 at low doses (MOI = 10), there was a significant increase in cell number with S-phase content (62.5%), which resulted in the most marked apoptosis induced by sequential treatments with flavopiridol. The sequential combination could induce significantly higher levels of p17 and p85 expression than that when their applications alone. Combined AdHTVP2G5-rev-casp3 and flavopiridol treatment prolonged mouse survival [mean survival time of (286 ± 6) days] and suppressed tumor growth significantly (tumor growth suppression rate of 81%), when compared with treatment using either alone. The levels of serum ALT and AST were not significantly elevated and no obvious lesions were found in any organs in treatments with AdHTVP2G5-rev-casp3 of low doses combined with flavopiridol.. AdHTVP2G5-rev-casp3 at low doses results in a significant increase in cell number with S-phase content, which significantly enhanced the sensitivity of cells to flavopiridol. Treatments of autocatalytic caspase-3 combined at low doses with flavopiridol result in significant synergistic antitumor effects, significant tumor growth suppression and prolonged survival of mice. When compared with normal dose flavopiridol alone, the combination could resulted in minimal liver toxicity.

Topics: Adenoviridae; Animals; Apoptosis; Caspase 3; Cell Cycle; Cell Line, Tumor; Cyclin-Dependent Kinases; Drug Synergism; Female; Flavonoids; Flow Cytometry; Gene Transfer Techniques; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Piperidines; Promoter Regions, Genetic; Survival Rate; Telomerase; Treatment Outcome; Xenograft Model Antitumor Assays

Multidrug resistance (MDR) is a major factor which contributes to the failure of cancer chemotherapy, and numerous efforts have been attempted to overcome MDR. To date, none of these attempts have yielded a tolerable and effective therapy to reverse MDR; thus, identification of new agents would be useful both clinically and scientifically.. To identify small molecule compounds that can reverse chemoresistance, we developed a 96-well plate high-throughput cell-based screening assay in a paclitaxel resistant ovarian cancer cell line. Coincubating cells with a sublethal concentration of paclitaxel in combination with each of 2,000 small molecule compounds from the National Cancer Institute Diversity Set Library, we identified a previously uncharacterized molecule, NSC23925, that inhibits Pgp1 and reverses MDR1 (Pgp1) but does not inhibit MRP or BCRP-mediated MDR. The cytotoxic activity of NSC23925 was further evaluated using a panel of cancer cell lines expressing Pgp1, MRP, and BCRP. We found that at a concentration of >10 microM NSC23925 moderately inhibits the proliferation of both sensitive and resistant cell lines with almost equal activity, but its inhibitory effect was not altered by co-incubation with the Pgp1 inhibitor, verapamil, suggesting that NSC23925 itself is not a substrate of Pgp1. Additionally, NSC23925 increases the intracellular accumulation of Pgp1 substrates: calcein AM, Rhodamine-123, paclitaxel, mitoxantrone, and doxorubicin. Interestingly, we further observed that, although NSC23925 directly inhibits the function of Pgp1 in a dose-dependent manner without altering the total expression level of Pgp1, NSC23925 actually stimulates ATPase activity of Pgp, a phenomenon seen in other Pgp inhibitors.. The ability of NSC23925 to restore sensitivity to the cytotoxic effects of chemotherapy or to prevent resistance could significantly benefit cancer patients.

Topics: Adenosine Triphosphatases; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Fluoresceins; Humans; Models, Chemical; Ovarian Neoplasms; Paclitaxel; Piperidines; Quinolines

This study was designed to determine the effects of vandetanib, a small-molecule receptor tyrosine kinase inhibitor of vascular endothelial growth factor and epidermal growth factor receptor, on paclitaxel (PTX) tumor distribution and antitumor activity in xenograft models of human ovarian carcinoma. Nude mice bearing A2780-1A9 xenografts received daily (5, 10, or 15 days) doses of vandetanib (50 mg/kg per os), combined with PTX (20 mg/kg intravenously). Morphologic and functional modifications associated with the tumor vasculature (CD31 and alpha-smooth muscle actin staining and Hoechst 33342 perfusion) and PTX concentrations in plasma and tumor tissues were analyzed. Activity was evaluated as inhibition of tumor growth subcutaneously and spreading into the peritoneal cavity. Vandetanib treatment produced no significant change in tumor vessel density, although a reduced number of large vessels, an increased percentage of mature vessels, and diminished tumor perfusion were evident. Pretreatment with vandetanib led to decreased tumor PTX levels within 1 hour of PTX injection, although 24 hours later, tumor PTX levels were comparable with controls. In efficacy studies, the combination of vandetanib plus PTX improved antitumor activity compared with vandetanib or PTX alone, with greater effects being obtained when PTX was administered before vandetanib. The combination of PTX plus vandetanib reduced tumor burden in the peritoneal cavity of mice and significantly increased their survival. Analysis of vascular changes and PTX tumor uptake in vandetanib-treated tumors may help to guide the scheduling of vandetanib plus PTX combinations and may have implications for the design of clinical trials with these drugs.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Mice; Mice, Nude; Neovascularization, Pathologic; Ovarian Neoplasms; Paclitaxel; Piperidines; Quinazolines; Tissue Distribution; Xenograft Model Antitumor Assays

To determine the effects of combining lonafarnib with paclitaxel on the growth of human ovarian cancer cells and tumor xenografts as well as to monitor a pharmacodynamic marker of farnesyltransferase inhibition (HDJ-2) in peripheral blood mononuclear cells (PBMCs) isolated from tumor-bearing animals after treatment with this combination.. Proliferation of A2780, PA-1, IGROV-1, and TOV-112D cells was assessed after treatment with lonafarnib and paclitaxel. Cell cycle progression was determined by flow cytometry, and apoptosis was evaluated by assaying for caspase-3 and cleaved PARP. The effects of lonafarnib and paclitaxel on the tumor growth of each model were determined in immunocompromised mice. Proteins extracted from cells, tumors, and PBMCs were assayed for HDJ-2 mobility shifts by Western blotting as well as for farnesyl protein transferase (FTase) enzyme activity by biochemical analyses.. In A2780, PA-1, IGROV-1, and TOV-112D cells lonafarnib potentiated the growth inhibitory effects of paclitaxel. In each of the models lonafarnib enhanced paclitaxel-induced mitotic arrest and apoptosis. The combination of lonafarnib plus paclitaxel resulted in marked tumor regressions in A2780, TOV-112D, PA-1, and IGROV-1 tumor xenografts. Western blotting demonstrated that in PBMCs isolated from the animals, paclitaxel treatment suppressed lonafarnib-induced HDJ-2 mobility shifts. Paclitaxel did not affect lonafarnib inhibition of FTase enzyme activity levels in these PBMCs.. Lonafarnib enhances the antiproliferative effects of paclitaxel on ovarian cancer cells in vitro and ovarian tumor xenografts in vivo. Measuring FTase enzyme activity levels rather than HDJ-2 shifts in PBMCs may be a more accurate biomarker to predict levels of farnesyltransferase inhibition in patients who are also receiving paclitaxel chemotherapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; Farnesyltranstransferase; Female; HSP40 Heat-Shock Proteins; Humans; Leukocytes, Mononuclear; Mice; Mice, Nude; Mice, SCID; Ovarian Neoplasms; Paclitaxel; Piperidines; Pyridines; Xenograft Model Antitumor Assays

To investigate the antitumor effect of flavopiridol in ovarian cancer.. After the treatment with flavopiridol of AO cells, cell apoptotic rate and cell cycle distribution were detected by flow cytometer and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL). Real time PCR was used to detect the expression of cyclin D and active caspase-3 in AO cells. Subcutaneous tumor models and abdominally spread tumor models of human ovarian carcinoma using AO cells in BALB/c nude mice were established. The mouse survival rates were measured for abdominally spread tumor models and the volume of tumor nodules was determined for subcutaneous tumor models following the treatments of flavopiridol. TUNEL was used to detect cell apoptosis, and immunohistochemistry was used to measure microvessel density (MVD) in tumor tissues.. AO cells showed apoptotic rates of 4.1%, 10.7% and 7.6% following the treatments with flavopiridol at 150, 300 and 500 nmol/L respectively, accompanied by an increase in G(1) progression and a decrease in S phase progression. The level of active caspase-3 increased (2.55 vs 2.49) and the level of cyclin D expression decreased significantly (0.25 vs 0.69, P < 0.05) after treatments with flavopiridol. Flavopiridol prolonged mouse survival [mean survival time of (141 +/- 14) days] and suppressed tumor growth significantly (tumor growth suppression rate of 40%), when compared with treatment using phosphate-buffered saline [(106 +/- 11) days, P < 0.05]. Apoptosis was detected in tumor tissues treated with flavopiridol. MVD of tumor tissue was 12 +/- 5 following flavopiridol treatment, significantly higher than that of 35 +/- 10 treated with phosphate-buffered saline (P < 0.05).. Flavopiridol results in significant suppression of ovarian carcinoma cell growth and prolongs survival of mice.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Cycle; Cell Line, Tumor; Cyclin D; Cyclin-Dependent Kinases; Cyclins; Dose-Response Relationship, Drug; Female; Flavonoids; Flow Cytometry; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Piperidines; Survival Analysis; Xenograft Model Antitumor Assays

A series of complexes of the general formula trans-[PtCl2(Am)(pip-pip)] x HCl where pip-pip is 4-piperidinopiperidine and Am is NH3, methylamine (MA), dimethylamine (DMA), n-propylamine (NPA), isopropylamine (IPA), n-butylamine (NBA), or cyclohexylamine (CHA) were prepared and characterized, and their cytotoxic properties against ovarian and colon cancer cells were evaluated. The trans-[PtCl2(NH3)(pip-pip)] x HCl was significantly more potent than cisplatin in all the cisplatin-resistant ovarian cancer cell lines and was nearly as cytotoxic as cisplatin against colon cancer cells. In vivo studies in mice showed that the pip-pip complexes are significantly less toxic than cisplatin. Cisplatin was more efficacious than both trans-[PtCl2(NH3)(pip-pip)] x HCl and trans-[PtCl2(NBA)(pip-pip)] x HCl in the A2780 and A2780cisR tumor xenograft models, consistent with its lower IC50 values in A2780 cells but contrary to the higher IC50 values in A2780cisR cells. In the colon cancer cell studies, trans-[PtCl2(NH3)(pip-pip)] x HCl was slightly less potent than cisplatin in the in vitro studies but had efficacy comparable to that of cisplatin in the in vivo xenograft model.

Topics: Amines; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Nucleus; Colonic Neoplasms; DNA; Drug Screening Assays, Antitumor; Female; Glucose; Humans; Ligands; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Organoplatinum Compounds; Ovarian Neoplasms; Piperidines; Sodium Chloride; Solubility; Solvents; Structure-Activity Relationship; Transplantation, Heterologous

Germ cell tumours (GCTs) are highly sensitive to cisplatin-based chemotherapy. The inability to arrest the cell cycle at the G1/S-check-point due to a lack of retinoblastoma gene product RB has been suggested as one potential explanation for this feature. Flavopiridol (FP), an inhibitor of cyclin dependent kinases, causes cell cycle arrest or apoptosis depending on the relation of the transcription factor E2F1 and RB.. The effect of FP was evaluated in GCT-derived cell lines NT2, 2102 EP and NCCIT in comparison to cell lines derived from ovarian cancer (SKOV), breast cancer (MCF7), and cervical cancer (HeLa) using the MTT-assay. Cell cycle progression and induction of apoptosis were assessed by flow cytometry and immunoblot analysis of PARP-cleavage.. FP did not affect cell cycle progression and proliferation of GCT cell lines at sublethal doses. At higher concentrations, cell death occurred independent of cell cycle progression. The IC50 was approximately fivefold lower for the three GCT cell lines (60/60/70 nM) than for the other tumour cell lines tested (350/280/300 nM). Lethal doses in vitro were markedly lower than plasma concentrations of FP achieved in clinical studies. In vitro sensitivity to FP did not correlate with that to cisplatin. The cell lines NTera2 and NCCIT showed comparable responses to FP despite differing in their IC50 to cisplatin by factor 4. Flow cytometry and immunoblot for PARP indicated apoptotic cell death induced by FP. Synergism between either cisplatin or paclitaxel and FP was not observed. However, at low concentrations, cytotoxicity of FP and cisplatin appeared to be additive.. These prelinical investigations suggest a significant antitumour activity of FP in GCT. GCT derived cell lines were far more responsive to FP than cell lines derived from other solid tumours. In contrast to other models, FP did not induce cell cycle arrest in the GCT-derived cell lines tested, possibly due to the known lack of RB-expression in GCTs. However, apoptosis was induced unrelated to cell cycle progression already at low concentrations. No cross resistance between FP and cisplatin was observed. A clinical trial evaluating the activity of FP in patients with cisplatin-refractory GCTs appears to be warranted.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Carcinoma, Embryonal; Cell Cycle; Cell Line, Tumor; Cisplatin; Dose-Response Relationship, Drug; Drug Synergism; Female; Flavonoids; Humans; Inhibitory Concentration 50; Ovarian Neoplasms; Paclitaxel; Piperidines; Uterine Cervical Neoplasms

Recently we reported that inhibition of cyclin-dependent kinases (cdks) by flavopiridol enhanced the radiation response of murine ovarian carcinoma cells in culture. The purpose of this investigation was to extend these studies to in vivo tumor models and test whether flavopiridol increases the therapeutic ratio of radiotherapy.. Three transplantable syngeneic mouse tumors were used: mammary carcinoma (MCa-29), ovarian carcinoma (OCa-I), and a lymphoma (Ly-TH). Tumor treatment endpoints included growth delay, cure, and spontaneous lung metastases (OCa-I tumor). The normal tissue endpoint was survival of jejunal crypt cells quantified microscopically. A range of flavopiridol doses from 0.625 to 5.0 mg/kg were given systemically once or twice daily over 5, 10, or 20 days. Combined therapy flavopiridol treatments were initiated either several days before or shortly after the start of single dose or daily fractionated radiotherapy.. The major findings of this study are that all three tumors treated with flavopiridol alone responded by tumor growth delay. Two of the tumors (MCa-29 and Ly-TH) responded in a schedule-dependent manner with larger radiation enhancement factors when flavopiridol treatment was started a few hours after irradiation (radioenhancement factors [EF] Ly-TH = 2.04, EF MCa-29 = 1.50 for single dose irradiation). When combined with fractionated irradiation (2.6 Gy daily for 10 or 20 days), flavopiridol enhanced the response of the MCa-29 tumor by a factor of 1.25-1.46. A fractional radiation dose of 6 Gy in combination with flavopiridol produced a 62.5% cure rate compared with 25% tumor cure for radiation alone. A novel finding of this study was the demonstration of antimetastatic activity of flavopiridol in addition to its effect on the local primary tumor. Both the incidence and absolute number of lung metastasis were reduced when flavopiridol followed surgical removal of the large (10 mm) primary leg tumor. The normal jejunum treated with flavopiridol and radiation responded in a schedule independent manner and the degree of radioenhancement (EF, 1.05-1.06) was much less than for any of the tumors studied.. Therapeutic gain was achieved when flavopiridol treatment was initiated either before or after the start of radiotherapy. Flavopiridol shows promising clinical potential administered alone or in combination with other cytotoxic agents, including both chemotherapy and radiotherapy.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cyclin-Dependent Kinases; Dose Fractionation, Radiation; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Female; Flavonoids; Jejunum; Lung Neoplasms; Mice; Mice, Inbred C3H; Ovarian Neoplasms; Piperidines; Radiation-Sensitizing Agents

The role of substance P in adverse pulmonary reactions induced by an anticancer agent paclitaxel was investigated in rats and humans who undertook post-operative chemotherapy for ovarian cancer. In rats, paclitaxel caused a marked plasma extravasation and edema in lungs with a concomitant decrease in arterial partial oxygen pressure, which were reversed by an NK1 antagonist LY303870. Substance P level in rat plasma and bronchoalveolar lavage fluid increased after paclitaxel injection. In 13 patients, plasma level of substance P but not histamine significantly (P < 0.05) increased during paclitaxel infusion. Therefore, substance P rather than histamine may be involved in paclitaxel hypersensitivity.

Topics: Animals; Antineoplastic Agents; Bronchoalveolar Lavage Fluid; Female; Histamine; Humans; Hypersensitivity; Indoles; Male; Neurokinin-1 Receptor Antagonists; Ovarian Neoplasms; Paclitaxel; Piperidines; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Retrospective Studies; Substance P

Flavopiridol, a cyclin-dependent kinase (cdk) inhibitor, can cause cell cycle arrest, induce apoptosis in cancer cells, and inhibit tumor cell growth in vivo. The present study investigated the in vitro radiosensitizing effect of flavopiridol and the underlying molecular mechanisms in a murine ovarian cancer cell line, OCA-I. Flavopiridol inhibited cell growth in a dose-dependent manner and enhanced cell radiosensitivity assessed by the clonogenic cell survival assay. A flavopiridol dose of 300 nM, given for 1 day, enhanced radiosensitivity by a factor of 2.1. Clonogenic cell survival after split-dose radiation showed that flavopiridol inhibited repair from radiation damage. In addition, flavopiridol treatment (300 nM, 1 day) resulted in decreased levels of Ku70 and Ku86 proteins that play a role in DNA repair processes, suggesting that DNA repair processes may have been disrupted by this agent. Flow cytometry analysis showed that flavopiridol (300 nM, 1 day) accumulated the cells in G(1) and G(2) phases, with a significant reduction in the S phase component. This cell cycle redistribution is likely another mechanism underlying flavopiridol-induced cell radiosensitivity. Flavopiridol down-regulated cyclin D1 and cyclin E protein levels and also inhibited phosphorylation of retinoblastoma protein, which is inconsistent with the observed cell cycle arrest. Among the cdks tested, cdk-9, the catalytic subunit of positive transcription elongation factor b, was significantly down-regulated by flavopiridol, suggesting that flavopiridol may modulate cellular transcription processes. Furthermore, flavopiridol on its own induced apoptosis in the OCA-I cells, whereas in combination with radiation, exerted no additional increase in apoptosis. Taken together, our data show that flavopiridol strongly augmented the response of ovarian carcinoma cells to radiation and that the underlying mechanisms included inhibition of sublethal DNA damage repair and cell cycle redistribution. At the molecular level, transcriptional regulation by flavopiridol may have been involved.

Topics: Animals; Antigens, Nuclear; Antineoplastic Agents; Apoptosis; Caspase 3; Caspases; Cell Cycle; Cyclin D1; Cyclin E; Cyclin-Dependent Kinases; DNA Helicases; DNA Repair; DNA-Binding Proteins; Drug Screening Assays, Antitumor; Enzyme Activation; Enzyme Inhibitors; Female; Flavonoids; Gamma Rays; Ku Autoantigen; Mice; Neoplasm Proteins; Ovarian Neoplasms; Piperidines; Radiation Tolerance; Radiation-Sensitizing Agents

Replacement of the ammine group in antitumor cisplatin by a heterocyclic ligand (piperidine, piperazine, or 4-picoline) results in reduction of cytotoxicity in human ovarian cancer cells. DNA is generally believed to be a major pharmacological target of antitumor platinum complexes. Therefore, we examined conformation of oligodeoxyribonucleotide duplexes containing a cross-link of cis-[PtCl(2)(NH(3))(piperidine)], their recognition by high mobility group proteins, and nucleotide excision repair; that is, some of the processes that may mediate antitumor effects of platinum drugs. The replacement does not affect the DNA binding mode including conformational alterations and excision of the cross-links. The results suggest that in certain cancer cells the lower cytotoxicity of cis-[PtCl(2)(NH(3))(piperidine)] might be partially associated with reduced affinity of the high mobility group proteins to the major intrastrand cross-links of this analogue relative to the same adducts of cisplatin. Besides this and a number of other biochemical factors, the reduced intracellular accumulation with subsequent effects on the level of DNA platination in the cells may also contribute to the reduced cytotoxicity of cis-[PtCl(2)(NH(3))(piperidine)]. The results support the view that the concept based on the design of the complexes structurally derived from cisplatin that do not present an altered DNA binding mode may be less effective in the search for new platinum drugs that would overcome cisplatin resistance.

Topics: Antineoplastic Agents; Base Sequence; Binding Sites; Cisplatin; Cross-Linking Reagents; DNA; DNA Adducts; DNA Repair; Female; High Mobility Group Proteins; Humans; Ligands; Oligodeoxyribonucleotides; Ovarian Neoplasms; Piperidines; Platinum Compounds; Sequence Analysis, DNA; Spain; Tumor Cells, Cultured

The aim of this study was to evaluate the role of endothelin-1 (ET-1) in the sensitivity of ovarian carcinoma to paclitaxel, one of the most common drugs used for the management of this tumour histotype. ET-1 is a powerful mitogenic peptide produced by ovarian carcinomas and it acts as an autocrine growth factor, selectively through ET(A) receptor (ET(A)R), which is predominantly expressed in this tumour. OVCA 433 and HEY, two ovarian carcinoma cell lines, which produce elevated amounts of ET-1 and express abundantly high-affinity ET(A)Rs, were used. As demonstrated by sub-G(1) peak in DNA content histograms and terminal transferase deoxytidyl uridine end labelling assay, we found that paclitaxel induces cytotoxic effect through the activation of apoptosis in both cell lines. When the treatment with paclitaxel was performed in association with ET-1, paclitaxel-induced apoptosis was inhibited. In order to evaluate which ET-1 receptor mediated the effect of ET-1 on protection from paclitaxel-induced apoptosis, we performed experiments using two selective antagonists for ET(A)R (BQ-123) and for ET(B)R (BQ-788). We showed that ET(A)R blockade inhibits the ET-1-induced survival activity against paclitaxel-mediated apoptosis. However, no effect was observed on blocking ET(B)R with BQ-788. Our results establish a novel role for ET-1 in determining survival of ovarian carcinoma cells and suggest that pharmacological ET(A)R blockade using a specific ET(A)R antagonist may provide a novel approach to the treatment of ovarian carcinoma in combination therapy.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Survival; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Oligopeptides; Ovarian Neoplasms; Paclitaxel; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Tumor Cells, Cultured

Endothelins (ETs) are a group of vasoactive peptides (ET-1, ET-2 and ET-3) produced by many cell types that bind to G-protein-linked transmembrane receptors, ET-A receptors (ET-RAs) and ET-B receptors (ET-RBs). These peptides are expressed in several human tumors, including carcinomas of the breast, and have a mitogenic effect in ovarian cancer cell lines. We investigated ET expression in infiltrating ductal carcinomas (IDCs) of the breast and the relationship between ET and hypoxia. ET staining was increased in human grade II IDC samples compared with normal breast tissue. ET-2 and ET-RB mRNA expression were absent in the majority of normal human breast samples (1 of 5 and 0 of 5, respectively) but was present in the majority of IDC tested (13 of 15 and 12 of 15, respectively). In a murine breast cancer model, HTH-K, ET-2, and ET-RB mRNA were detected in tumor but not normal breast tissue, and ET expression colocalized with areas of hypoxia. In vitro, ET-2, ET-RA, and ET-RB mRNA were increased by incubating HTH-K cells in hypoxia (0.1% oxygen) for 24 h. Hypoxia also up-regulated ET-2 mRNA in several human breast tumor cell lines. ET-2 mRNA increased within 3 h in a hypoxia-inducible factor 1-dependent manner. The ET-RB antagonist BQ-788 increased in hypoxia-associated apoptosis of breast tumor cells in vitro. These effects could be reversed by addition of ET-2 peptide. Intratumoral injection of BQ-788 led to an increase in the development and extent of necrosis within the HTH-K tumor and a decrease in the rate of tumor growth. The ET-RA antagonist, BQ-123, also led to a decrease in tumor growth but without a concomitant increase in necrosis. We propose that modulation of ET-2 production via the hypoxia-inducible factor 1 transcription factor and autocrine signaling via ET-RB is a novel mechanism by which tumor cells can withstand hypoxic stress. Treatment of breast carcinomas with ET receptor antagonists may have a therapeutic benefit.

Topics: Antihypertensive Agents; Blotting, Northern; Breast Neoplasms; Cell Survival; DNA-Binding Proteins; Dose-Response Relationship, Drug; Endothelin-2; Female; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Necrosis; Nuclear Proteins; Oligopeptides; Ovarian Neoplasms; Peptides, Cyclic; Piperidines; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Time Factors; Transcription Factors; Tumor Cells, Cultured; Up-Regulation

Flavopiridol, the first inhibitor of cyclin-dependent kinases to enter clinical trials, has shown promising antineoplastic activity and is currently undergoing Phase II testing. Little is known about mechanisms of resistance to this agent. In the present study, we have characterized an ovarian carcinoma cell line [OV202 high passage (hp)] that spontaneously developed drug resistance upon prolonged passage in tissue culture. Standard cytogenetic analysis and spectral karyotyping revealed that OV202 hp and the parental low passage line OV202 shared several marker chromosomes, confirming the relatedness of these cell lines. Immunoblotting demonstrated that OV202 and OV202 hp contained similar levels of a variety of polypeptides involved in cell cycle regulation, including cyclin-dependent kinases 2 and 4; cyclins A, D1, and E; and proliferating cell nuclear antigen. Despite these similarities, OV202 hp was resistant to flavopiridol and cisplatin, with increases of 5- and 3-fold, respectively, in the mean drug concentrations required to inhibit colony formation by 90%. In contrast, OV202 hp and OV202 displayed indistinguishable sensitivities to oxaliplatin, paclitaxel, topotecan, 1,3-bis(2-chloroethyl)-1-nitrosourea, etoposide, doxorubicin, vincristine, and 5-fluorouracil, suggesting that the spontaneously acquired resistance was not attributable to altered P-glycoprotein levels or a general failure to engage the cell death machinery. After incubation with cisplatin, whole cell platinum and platinum-DNA adducts measured using mass spectrometry were lower in OV202 hp cells than OV202 cells. Similarly, after flavopiridol exposure, whole cell flavopiridol concentrations measured by a newly developed high performance liquid chromatography assay were lower in OV202 hp cells. These data are consistent with the hypothesis that acquisition of spontaneous resistance to flavopiridol and cisplatin in OV202 hp cells is due, at least in part, to reduced accumulation of the respective drugs. These observations not only provide the first characterization of a flavopiridol-resistant cell line but also raise the possibility that alterations in drug accumulation might be important in determining sensitivity to this agent.

Topics: Antineoplastic Agents; Carmustine; Chromosome Aberrations; Chromosome Mapping; Cisplatin; DNA Adducts; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Flavonoids; Humans; Karyotyping; Organoplatinum Compounds; Ovarian Neoplasms; Oxaliplatin; Piperidines; Tumor Cells, Cultured

SCH66336 is a p.o.-active, farnesyl protein transferase inhibitor. SCH66336 inhibits farnesylation of RAS and other proteins in tumor cells and suppresses tumor growth in human xenograft and transgenic mouse cancer models in vivo. SCH58500 is a replication-deficient, recombinant adenovirus, which expresses the human p53 tumor suppressor. In preclinical models, SCH58500 has therapeutic efficacy against a wide range of human tumor types containing nonfunctional p53 and enhanced activity in combination with many chemotherapeutic drugs. Here we report that combination therapy with SCH66336 and SCH58500 has synergistic or additive antiproliferative effects on a panel of tumor cells lines in vitro. The efficacy of the three-drug combination of SCH66336, SCH58500, and paclitaxel was also examined in vitro. Each two-drug interaction displayed such marked synergy, the addition of a third drug to the statistical model could only yield additivity. Greater combined efficacy for SCH66336 and SCH58500 was also observed in vivo in the DU-145 human prostate and wap-ras/F transgenic mouse cancer models.

Topics: Adenocarcinoma; Adenoviruses, Human; Alkyl and Aryl Transferases; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Survival; Drug Synergism; Female; Genes, ras; Humans; Male; Mice; Mice, Nude; Mice, SCID; Mice, Transgenic; Ovarian Neoplasms; Paclitaxel; Pancreatic Neoplasms; Piperidines; Prostatic Neoplasms; Pyridines; Teratocarcinoma; Tumor Cells, Cultured; Tumor Suppressor Protein p53

To elucidate the potential role of endothelins (ETs) as growth regulators in ovarian carcinoma cells in culture, expression of endothelins and their receptors were measured in two ovarian cancer cell lines (PEO4 and PEO14), together with the effect of the exogenous addition of endothelins on the growth of these cell lines in vitro. RT-PCR analysis of mRNA prepared from PEO4 and PEO14 indicated the presence of ET-1 and ET-3 mRNA. Immunoreactive ET-1-like peptide was found in media from cultures of both PEO4 (1.7 +/- 0.4 fmol/10(6) cells/72 h) and PEO14 (20.2 +/- 6.8 fmol/10(6) cells/72 h) cell lines. Radioligand binding studies using 125I-ET-1 and membrane fractions were consistent with PEO4 cells having two receptor sites of either high affinity (Kd = 0.065 nM, Bmax = 0.047 pmol/mg protein) or lower affinity sites (Kd = 0.49 nM, Bmax = 0.23 pmol/mg protein). Studies using membrane fractions of PEO14 cells indicated that this cell line has only a single lower affinity binding site (Kd = 0.56 nM, Bmax = 0.31 pmol/mg protein). However, RT-PCR analysis indicated the presence of mRNA from both ETA and ETB receptors in PEO4 and PEO14 cell lines. Exogenous addition of ETs to PEO4 and PEO14 cells at concentrations of 10(-10)-10(-7)M resulted in specific dose-dependent increases in cell number for ET-1 (with maximum effects at 10(-10) and 10(-9)M for PEO4 and PEO14, respectively) and ET-2 (maximum effects at 10(-8) and 10(-9)M for PEO4 and PEO14, respectively) but not for ET-3. Experiments on the growth of PEO14 cells using BQ123 (ETA-R) antagonist and "antisense" oligonucleotide against the ETA-R, in the absence of exogenous ETs, suggested that immunoreactive ET-1-like material secreted by PEO14 cells can affect their growth in an autocrine manner. These results would be consistent with ET-1 acting as a possible autocrine growth regulator in human ovarian carcinoma cells.

Topics: Cell Division; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelin-3; Endothelins; Female; Humans; Oligopeptides; Ovarian Neoplasms; Peptides, Cyclic; Piperidines; Polymerase Chain Reaction; Protein Binding; Receptors, Endothelin; RNA, Messenger; Tumor Cells, Cultured

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Drugs, Investigational; Estrogen Antagonists; Female; Humans; Lavandula; Male; Neoplasms; Oils, Volatile; Ovarian Neoplasms; Piperidines; Plant Oils; Plants, Medicinal; Prostatic Neoplasms; Raloxifene Hydrochloride; Retinoids; Tamoxifen; Toremifene

Ether lipid analogues of platelet-activating factor (1-octadecyl-2-acetyl-sn-glycero-3-phosphocholine) possess a wide range of biological activities, including inhibition of neoplastic cell growth in vitro and in vivo. This activity is believed to be membrane mediated. Three different ether lipid analogues, 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine, 1-thiohexadecyl-2-ethyl-rac-glycero-3-phosphocholine, and 4-amino-methyl-1-[2,3-(di-n-decyloxy)-n-propyl]-4-phenylpiperidine , were combined with three DNA-interactive drugs, Adriamycin, 4-hydroperoxycyclophosphamide, and cisplatin, in the expectation that combinations of drugs with different mechanisms of action might show enhanced antitumor activity. The in vitro antiproliferative activity of the combinations was measured with a semisoft agarose clonogenic assay of an ovarian adenocarcinoma cell line. Various permutations of drug combinations were studied. Isobologram analyses and different treatment schedules were performed. Enhanced antiproliferative activity was found with combinations of ether lipids with DNA-interactive drugs in comparison with single agents. Statistical evaluation of the data indicated that the increase in activity was due to an additivity phenomenon. Neither synergism nor antagonism was found.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Cell Survival; Cisplatin; Cyclophosphamide; Doxorubicin; Female; In Vitro Techniques; Ovarian Neoplasms; Phospholipid Ethers; Piperidines; Tumor Cells, Cultured