piperidines and Endometrial-Neoplasms

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

The selective estrogen receptor modulators (SERMs) are substances with estrogenic/anti-estrogen effect that act differently depending on the tissue and composition. Since the discovery that tamoxifen and raloxifene (RLX) had a breast cancer preventive effect, the search for the perfect SERM has been the goal. The evidence that tamoxifen significantly increased the risk of endometrial cancer as compared to placebo made this tissue the center of interest in developing new SERMs. Thus, ospemifen, arzoxifene, lasofoxifene (LFX) and bazedoxifene (BZA) appeared as third-generation SERMs but only BZA reached the stage of clinical use. Both experimental and clinical data available on the effects of RLX or third-generation SERMs reaching clinical stage (LFX and BZA) show either neutrality or anti-estrogenic effects at endometrial level. BZA has shown to be equivalent to vehicle in several experimental conditions and acts as anti-estrogen in models were estrogens (conjugated equine estrogens [CEE] or E2) were co-administered. In a 7 years pivotal study the incidence of endometrial adenocarcinoma has been significantly lower in the BZA than in the placebo group. Moreover, in a clinical trial to evaluate the ability of a combination of BZA and CEE to prevent hot flushes in symptomatic postmenopausal women, doses of 20mg or higher of BZA have significantly decreased the risk of presenting endometrial hyperplasia when co-administered with either 0.650 or 0.450mg of CEE.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation, Preclinical; Endometrial Neoplasms; Endometrium; Estradiol; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Hot Flashes; Humans; Indoles; Menopause; Multicenter Studies as Topic; Organ Specificity; Osteoporosis, Postmenopausal; Piperidines; Pyrrolidines; Rats; Selective Estrogen Receptor Modulators; Tamoxifen; Tetrahydronaphthalenes; Thiophenes; Thromboembolism

Hormone-sensitive tumours are among the most common cancers in women. Specific inhibition of the estrogen receptor by selective estrogen receptor downregulators or selective estrogen receptor modulators (SERMs) is effective for the treatment of breast and endometrial cancers and may be used for the prevention of breast cancer. Due to differential recruitment of co-activators and corepressors, SERMs are tissue specific and may have antiestrogenic effects in some tissues, with estrogen agonist activity in others. The ideal SERM would have antiestrogenic effects on the breast and endometrium, but pro-estrogenic effects on bone and lipids. The SERM, arzoxifene (LY-353381.HCl) meets all of these criteria. This review summarises the development, preclinical studies and the clinical outcome of arzoxifene and places it in context with other modalities in the treatment of hormone receptor-positive tumours.

Topics: Animals; Breast Neoplasms; Endometrial Neoplasms; Female; Humans; Piperidines; Randomized Controlled Trials as Topic; Selective Estrogen Receptor Modulators; Thiophenes; Treatment Outcome

Arzoxifene, an orally active third-generation selective estrogen-receptor modulator (SERM), opposes the action of estrogen on the breast and endometrium but exerts an estrogen-agonist effect on bone and the lipid profile. Since this is an appealing combination for hormonal therapy of estrogen-related cancers, we initiated testing the potential of arzoxifene in women with treatment-refractory endometrial cancer.. Two phase I studies were conducted to evaluate the safety and pharmacokinetics of single and multiple doses of arzoxifene. In addition, two multi-institutional phase II trials have been completed on 100 women with metastatic or recurrent endometrial cancer.. No serious adverse events were observed in the single-dose phase I study, the principal side effect being hot flashes in 5/15 healthy volunteers. In the second phase I study, conducted in 32 women with metastatic breast cancer, one patient had a serious, possibly drug-related adverse reaction (pulmonary embolism). The two multi-institutional trials demonstrated significant activity at 20 mg/day in patients with metastatic or recurrent endometrial cancer. Observed clinical response rates were 25 and 31%, with a median response duration of 19.3 and 13.9 months, respectively. Progression of the disease was stabilized in a substantial number of women. Toxicity was mild, except for two cases of pulmonary embolism that might have been drug related.. Further investigation is warranted to verify these preliminary response rates and the clinical significance of the stable disease cases, to compare clinical outcomes with those in progestin-treated women, and to elucidate the mechanisms of SERM action in this disease.

Topics: Antineoplastic Agents, Hormonal; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Endometrial Neoplasms; Female; Humans; Multicenter Studies as Topic; Piperidines; Selective Estrogen Receptor Modulators; Thiophenes

The understanding of how estrogen affects different body tissues by selective actions on the two subtypes of estrogen receptors (alpha and beta) has created the possibility of targeted therapy by the manufacturing of a group of compounds known as selective estrogen receptor modulators. The goal of an ideal selective estrogen receptor modulator that has all the beneficial effects of estrogen receptor modulation without adverse side effects seems increasingly achievable with improving drug design. The clinical findings for the new selective estrogen receptor modulator, arzoxifene, which has been shown to be highly active in the treatment of advanced breast cancer as well as advanced endometrial cancer, has confirmed the value of selective targeting of the estrogen receptors, and may herald a new era in endocrine therapy in clinical oncology.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Endometrial Neoplasms; Estradiol; Female; Fulvestrant; Humans; Piperidines; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Thiophenes

The median survival of women with advanced or recurrent endometrial cancer is less than one year. Only half the women with early stage endometrial cancer and poor prognostic factors such as high grade or deep myometrial invasion will survive for 5 years. Over the past decade, incredible strides have been taken in evaluating systemic therapy for this disease. However, survival rates remain poor. A literature search was conducted using CANCERLIT, EMBASE, Medline, Investigational Drug database (Current Drug Ltd.) and R&D Focus (IMSworld Publications). The references of the articles were also explored. Search terms included: endometrial cancer, chemotherapy, endocrine/hormonal therapies, molecular biologics, and specific drug names. Progestin therapy offers a 10-20% response rate and survival of less than 1 year. Progestins are most effective in women with well-differentiated tumours and a long disease-free interval. There is no role for adjuvant progestin therapy in early stage disease. Single-agent chemotherapy with the most activity includes ifosfamide, cisplatin/carboplatin, doxorubicin and paclitaxel. Combination chemotherapy provides a response rate of 40-60%; however, median survival is still less than a year. New areas of research include the identification and evaluation of new active endocrine therapies (i.e. LY353381.HCl and letrozole), chemotherapeutics (i.e. herceptin), evaluating chemotherapeutic agents in combination (i.e. paclitaxel, doxorubicin and platinum), in addition to radiation or instead of radiation. New avenues under development involve the specific molecules and pathways responsible for the initiation and growth of endometrial carcinoma, including: tumour suppressor genes, DNA mismatch repair genes, oncogenes, molecules involved in adhesion and invasion and angiogenesis. Further significant advances in radiotherapy, hormonal therapy and chemotherapy are unlikely. Exciting developments in understanding the molecules involved in tumour development and metastasis will allow the development of specific and selective inhibitors.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Endometrial Neoplasms; Female; Genes, Tumor Suppressor; Humans; Neoplasm Staging; Phosphoric Monoester Hydrolases; Piperidines; Progestins; PTEN Phosphohydrolase; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Survival Rate; Thiophenes; Tumor Suppressor Proteins

In order to minimize the risks of endometrial cancer and the development of resistance to antiestrogen therapy, we have synthesized the orally active antiestrogen EM-652 which is the most potent of the known antiestrogens and exerts pure antiestrogenic activity in the mammary gland and endometrium. EM-652 inhibits the AF-1 and AF-2 functions of both ERalpha and beta while the inhibitory action of OH-TAM is limited to AF-2. EM-652, thus, inhibits Ras-induced transcriptional activity and blocks SRC-1-stimulated activity of the two receptors. The absence of blockade of AF-1 by OH-TAM could explain why resistance develops to Tamoxifen treatment. Not only the development, but also the growth of established DMBA-induced mammary carcinoma is inhibited by treatment with EM-800, the prodrug of EM-652. EM-652 is the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro. When incubated with human Ishikawa endometrial carcinoma cells, EM-800 has no stimulatory effect on the estrogen-sensitive parameter alkaline phosphatase activity. When administered to ovariectomized animals, EM-800 prevents bone loss, and lowers serum cholesterol and triglyceride levels. EM-800 has shown benefits in women with breast cancer who had failed Tamoxifen. The above-summarized preclinical and clinical data clearly suggest the interest of studying this compounds in the neoadjuvant and adjuvant settings and, most importantly, for the prevention of breast and uterine cancer.

Topics: Animals; Benzopyrans; Breast; Breast Neoplasms; Cholesterol; Endometrial Neoplasms; Endometrium; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptor Modulators; Female; Humans; Mammary Neoplasms, Experimental; Mice; Neoplasms, Hormone-Dependent; Osteoporosis; Piperidines; Propionates; Rats; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen; Transcription, Genetic; Triglycerides; Tumor Cells, Cultured

The recently completed Breast Cancer Prevention Trial found that tamoxifen can reduce the incidence of breast cancer by nearly half in women at high risk, but the benefit comes at a price of increased risk of endometrial cancer and thromboembolism. This article reviews the actions of tamoxifen and the design, findings, and implications of this study.

Topics: Adolescent; Adult; Aged; Breast Neoplasms; Chemotherapy, Adjuvant; Drug Approval; Endometrial Neoplasms; Estrogen Antagonists; Female; Humans; Middle Aged; Patient Selection; Piperidines; Prospective Studies; Raloxifene Hydrochloride; Risk Assessment; Tamoxifen; United States; United States Food and Drug Administration

In spring 1998, breast cancer prevention emerged from being a concept to being a reality. The National Surgical Adjuvant Breast and Bowel Project prevention trial showed that tamoxifen reduced breast cancer by 45% in high-risk women between the ages of 35 and 75. Additionally, an evaluation of 10,550 patients randomized to osteoporosis trials of placebo versus raloxifene demonstrated a 50% reduction in the incidence of breast cancer in woman taking raloxifene. For the future, a Study of Tamoxifen Against Raloxifene (STAR) is ongoing in high-risk postmenopausal women. This chapter describes the biological rationale for the current clinical advances.

Topics: Adult; Aged; Animals; Breast Neoplasms; Endometrial Neoplasms; Estrogen Antagonists; Female; Humans; Middle Aged; Piperidines; Postmenopause; Raloxifene Hydrochloride; Rats; Tamoxifen

Various ongoing double-blind clinical trials are evaluating the use of tamoxifen (Nolvadex) as chemoprevention for breast cancer. A total of over 24,000 healthy women have been randomized to these trials, and it should be possible, by the year 2000, to detect any preventive effect of tamoxifen in healthy women. Furthermore, with the large numbers of women involved, it should be possible to evaluate prevention in subgroups of participants according to risk of the disease, particularly those women carrying high-risk genes, such as BRCA1 and BRCA2. Adverse effects of tamoxifen have been identified, including a transient bone loss in premenopausal women and uterine effects, including polyps, cysts, and endometrial cancer, in postmenopausal women. Although the potential benefit of tamoxifen in preventing breast cancer in healthy women is likely to outweight any potential long-term risks, the use of other tamoxifen-like drugs, such as raloxifene (Evista) and toremifene (Fareston) is now being investigated.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Double-Blind Method; Endometrial Neoplasms; Estrogen Antagonists; Female; Genes, BRCA1; Humans; Italy; Neoplasms, Hormone-Dependent; Osteoporosis, Postmenopausal; Piperidines; Raloxifene Hydrochloride; Tamoxifen; Toremifene; United Kingdom; United States

To guarantee efficient operating room (OR) activity, tracheal extubation is often performed in the postanesthesia care unit (PACU). Therefore, the ability of PACU to accommodate postoperative patients is crucial. Optimizing extubation management may speed up the turnover of PACU beds. The aim of the present study was to investigate the effect of remifentanil, which is used during analepsia, on the length of PACU stay in patients undergoing laparoscopic surgery for endometrial cancer.. In this prospective trial, we recruited a total of 99 patients, who were scheduled for laparoscopic surgery for endometrial cancer. At the end of the surgery, all patients were immediately transferred to the PACU and continued mechanical ventilation. Upon PACU admission, sputum aspiration was routinely performed. If the hemodynamic parameters fluctuated >30% of the baseline level, or patients moved unconsciously without reaching the criteria of extubation, a bolus injection of either 1 μg/kg remifentanil (Rem group, n=51) or propofol 1.0 mg/kg (Pro group, n=48) was randomly administered. The primary outcome was the duration of PACU stay. The secondary outcomes included time to respiratory breath recovery and time to extubation, along with bispectral index (BIS) values and hemodynamic status after remifentanil or propofol intervention. Times of repeated intervention, rescue administration of vasoactive drugs, and the incidence of adverse events were recorded. Visual analog scale and satisfaction scores at the time of PACU discharge were also evaluated.. The duration of PACU stay was shorter in the Rem group than in the Pro group [49 (46.47-51.06 minutes) vs. 62 minutes (60.75-69.29 minutes), P<0.0001]. Compared with the Pro group, the time to spontaneous breathing recovery, the time to extubation, and the incidence of hypoxemia after extubation were reduced in the Rem group (P<0.0001, P<0.0001, P=0.03, respectively). After anesthetic administration, the BIS value decreased less in the Rem group (P<0.0001); blood pressure and heart rate (HR) declined, but were comparable in both groups.. Remifentanil, which is injected during analepsia, significantly shortens the duration of PACU stay without increasing adverse events in the peri-extubation period.

Topics: Anesthetics, Intravenous; Endometrial Neoplasms; Female; Humans; Laparoscopy; Piperidines; Prospective Studies; Remifentanil

The aim of this study was to report the gynecologic safety findings from the Generations trial, a phase 3 study of the selective estrogen receptor modulator (SERM), arzoxifene.. A predefined objective of the trial was to evaluate the effects of arzoxifene on the genital tract. Gynecologic examinations were performed yearly, and further gynecologic assessment, including endometrial biopsy, was performed in a predefined subset of women and in those who developed vaginal bleeding.. Overall, 9,354 women were randomized (4,678 to placebo, 4,676 to arzoxifene 20 mg/d). There were 13 adjudicated cases of endometrial cancer (placebo, 4 cases; arzoxifene, 9 cases: P = 0.165) and 6 cases of endometrial hyperplasia (placebo, 2 cases; arzoxifene, 4 cases). Endometrial thickness, assessed at 24- and 36-month transvaginal ultrasounds in a subset of women, increased slightly in women assigned to arzoxifene compared with baseline and women in placebo. At the last measurement, 3 (1.7%) women assigned to placebo and 21 (10.2%) assigned to arzoxifene had an endometrial thickness greater than 5 mm (P < 0.001 for difference between treatment groups). Endometrial polyps were more common in women treated with arzoxifene (n = 37) than in women treated with placebo (n = 18; P < 0.05). Vulvular and vaginal inflammation, including mycotic infections, and vaginal discharge were reported more frequently in women treated with arzoxifene than in women treated with placebo, as were urinary tract infections.. Gynecologic events were generally more common in women treated with arzoxifene than in women treated with placebo. The gynecologic effects of arzoxifene seem to differ from those of raloxifene, although both SERMs have a benzothiophene structure. Although all SERMs influence cells through the estrogen receptor, they need to be evaluated independently in terms of their effects on various tissues, including the genital tract.

Topics: Aged; Aged, 80 and over; Endometrial Neoplasms; Endometrium; Female; Genital Diseases, Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Piperidines; Placebos; Polyps; Postmenopause; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Thiophenes; Uterine Hemorrhage; Vaginitis; Vulvitis

The effect of surgery and anesthesia on the immune response may have a significant effect on perioperative tumor surveillance. The aim of this study was to characterize the cellular immune response of patients undergoing simple abdominal hysterectomy under 3 types of anesthesia.. ASA 1-2 patients undergoing simple abdominal hysterectomy were enrolled prospectively after they gave informed consent; the patients were randomized to 3 groups of 20 each to receive balanced anesthesia (group A), remifentanil-based anesthesia and analgesia (group B), or combined general-epidural anesthesia (group C). Postoperative analgesia was provided in accordance with group assignment. Four and 24 hours after surgery, 20 mL of blood was drawn from each patient for analysis of leukocyte populations and lymphocyte subpopulations. Statistics were calculated with the SPSS software package, version 12.0.. All groups had elevated neutrophil counts after surgery; the lowest levels were in group C (P<.05). Patients in all 3 groups developed lymphopenia, which was still evident 24 hours after surgery (P<.05). CD3 cell counts at 4 hours were lowest in patients who had received combined anesthesia (group C), CD19 cell counts were highest in group A, and CD16 cell counts were lowest in group C; this last difference was maintained at 24 hours (P<.05 for all these comparisons).. Combined general-epidural anesthesia seems to lower the counts of natural killer cells that are involved in tumor surveillance and destruction.

Topics: Adenocarcinoma; Analgesia; Analgesia, Epidural; Analgesics; Anesthesia, Epidural; Anesthesia, General; Anesthetics, General; Endometrial Neoplasms; Female; Fentanyl; Humans; Hysterectomy; Immunologic Surveillance; Killer Cells, Natural; Lymphocyte Subsets; Lymphopenia; Methyl Ethers; Middle Aged; Morphine; Piperidines; Postoperative Complications; Prospective Studies; Remifentanil; Sevoflurane

A phase II study was conducted to determine the efficacy of single agent flavopiridol therapy in patients with recurrent or persistent endometrial adenocarcinoma refractory to established treatments.. Eligible patients with measurable disease who failed primary therapy including one cytotoxic regimen were eligible for the trial. They were treated with single agent flavopiridol (50 mg/m(2)/day, IV bolus days 1, 2, 3). Treatment was repeated every 21 days with dose adjustments made for toxicity. Patients were treated until progression of disease or adverse side effects precluded further therapy.. A total of 26 patients were enrolled in the study of whom, 23 patients were eligible. There were no objective responses. Five patients had stable disease (22%), 15 (65%) had increasing disease, and response could not be assessed in 3 (13%). The most frequent side effects included anemia, neutropenia, and diarrhea, all of which appeared manageable.. Flavopiridol as a single agent in the above dosing schedule appears to have minimal activity as second-line chemotherapy of endometrial adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Endometrial Neoplasms; Female; Flavonoids; Humans; Middle Aged; Neoplasm Recurrence, Local; Piperidines

The goal of this study was to determine response rate and evaluate toxicity of LY353381 (arzoxifene) in patients with recurrent or advanced endometrial cancer (EC).. A phase II, open-labeled study with arzoxifene was performed at 13 centers. Patients with measurable recurrent/advanced EC not amenable to curative therapies were eligible if either the primary tumor or recurrent tumor was ER+ and/or PR+. If receptor status could not be determined, patients with well or moderately well-differentiated EC were also permitted. Prior use of salvage chemotherapy was not allowed; however, prior use of progestagens was permitted and patients were stratified by prior exposure to progestagen. Patients received 20 mg/day PO, and were treated for at least 8 weeks in the absence of disease progression or unacceptable toxicity. Efficacy was based on the frequency of complete (CR) and partial (PR) responses, and a 95% confidence interval (CI) was calculated. The Kaplan-Meier method was used to analyze time to progression and duration of response.. From February 1999 through April 2001, 37 patients were entered of whom 34 received treatment. Efficacy was evaluated for the 29 patients who received at least 4 weeks of therapy and at least one tumor response assessment. Safety was assessed in all 34 patients who received any drug. Thirty patients were defined as progestagen sensitive, and 4 patients were defined as progestagen failures. Twenty-six patients were ER+, and 22 were PR+. Nine (1 CR + 8 PR) of 29 patients responded (31%, CI 25-51%), with a median duration of response of 13.9 months. All 9 responses occurred in progestagen-sensitive patients. Two additional patients (one from each progestagen cohort) had stable disease for >or=6 months. The median progression-free interval was 3.7 months (CI 1.9-6.6 months) for all 29 patients. Toxicity was minimal with no grade 3-4 toxic effects, and 9 patients had only grade 1-2 toxic effects (7 grade 1, 2 grade 2). Hot flashes were the most common toxic effect and, in all 3 reported cases, were grade 1.. Arzoxifene has demonstrated a high response rate with the longest median duration of response reported in a phase II trial of this patient population. The ease of administration and extremely favorable toxicity profile make this an agent warranting further evaluation.

Topics: Adult; Aged; Aged, 80 and over; Disease-Free Survival; Endometrial Neoplasms; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Selective Estrogen Receptor Modulators; Thiophenes

Raloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting.. To determine whether women taking raloxifene have a lower risk of invasive breast cancer.. The Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe.. A total of 7705 postmenopausal women, younger than 81 (mean age, 66.5) years, with osteoporosis, defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women. Almost all participants (96%) were white. Women who had a history of breast cancer or who were taking estrogen were excluded.. Raloxifene, 60 mg, 2 tablets daily; or raloxifene, 60 mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets.. New cases of breast cancer, confirmed by histopathology. Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women. Deep vein thrombosis or pulmonary embolism were determined by chart review.. Thirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P<.001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor-positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24), but not estrogen receptor-negative invasive breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7).. Among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene.

Topics: Aged; Breast Neoplasms; Double-Blind Method; Endometrial Neoplasms; Estrogen Antagonists; Estrogens; Female; Follow-Up Studies; Humans; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Raloxifene Hydrochloride; Receptors, Estrogen; Risk; Thromboembolism

Endometrial cancer (EC) is the second most common gynecologic malignancy in China, and the incidence and mortality rates have increased in recent years. Brain metastasis from EC is extremely rare, affecting only 0.3-1.16% of EC patients. The prognosis for patients with brain metastasis from EC is poor, with a median survival time of 3.5-6.5 months from the diagnosis of brain metastasis. Niraparib is a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that uses the concept of synthetic lethality in the presence of a mutation in the breast cancer susceptibility gene (BRCA). Niraparib is recommended as a maintenance treatment for ovarian cancer patients with platinum-sensitive relapse and has been shown to increase progression-free survival. Niraparib was found to enter the brain via the blood-brain barrier, which resulted in a higher concentration of the drug in the brain tissues and better tumor-suppressing effects. There was none report about the applications of PARP inhibitor for endometrial cancer with brain metastases. Here, we present the case of a 62-year-old woman whose Peripheral blood gene detection had shown BRCA1 mutation with brain metastases from high-grade serous carcinoma of the endometrium who was successfully treated with Niraparib and remained free of disease progression for 6 months.

Topics: Brain Neoplasms; China; Endometrial Neoplasms; Female; Humans; Indazoles; Middle Aged; Piperidines

Abnormal lipid metabolism plays a dual role in tumorigenesis, specifically in the occurrence and development of cancers. Monoacylglycerol lipase (MAGL), a hydrolase that is important for lipid metabolism, plays a vital role in different aspects of tumorigenesis. Many studies have shown that MAGL is highly elevated in a variety of cancers and plays an active role. However, its potential role in supporting endometrial cancer (EC) growth and progression has not yet been explored in depth.. Immunohistochemistry and quantitative real-time reverse transcription polymerase chain reaction were performed to estimate the protein and messenger RNA (mRNA) levels of MAGL in tumor tissues. Then, JZL184 and small interfering RNA (siRNA) were used to decrease the expression of MAGL in EC cells. The gene and protein expression levels of MAGL were measured using quantitative real-time PCR and western blotting, respectively. Additionally, the effect of MAGL on tumor growth in EC was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide , cell cycle and western blotting assay in vitro.. We found that MAGL was overexpressed in EC and was significantly correlated with surgical-pathological stage, myometrial invasion, number of pregnancies and body mass index. The growth and cell cycle progression of tumor cells were significantly impaired in vitro by the pharmacological and siRNA-mediated MAGL inhibition. In addition, MAGL inhibition seemed to repress two target genes, Cyclin D1 and Bcl-2.. In summary, we have demonstrated that MAGL is involved in EC growth and progression. Our results suggest that targeting MAGL may be a novel and valid treatment for EC.

Topics: Adenocarcinoma; Adult; Aged; Benzodioxoles; Cell Cycle; Cyclin D1; Drug Screening Assays, Antitumor; Endometrial Neoplasms; Female; Humans; Middle Aged; Molecular Targeted Therapy; Monoacylglycerol Lipases; Piperidines; Proto-Oncogene Proteins c-bcl-2

Gynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin.. We analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer.. We first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin.. Our findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Carcinoma, Endometrioid; Chemotherapy, Adjuvant; Cisplatin; Disease-Free Survival; Doxorubicin; Endometrial Neoplasms; Female; Humans; Hysterectomy; Immunohistochemistry; Middle Aged; Neoplasm Staging; Paclitaxel; Piperidines; Prognosis; Retrospective Studies; Stathmin; Survival Rate

Endometrial carcinoma is one of the most common malignancies of the female reproductive system, but the aetiology and pathogenesis are not well understood, although adipokines such as visfatin may be involved. Our study provides insight into the mechanism underlying the tumorigenic effects of visfatin in endometrial carcinoma.. We investigated the effect of visfatin on endometrial carcinoma cell proliferation, cell cycle, and apoptosis using well-differentiated Ishikawa cells and poorly differentiated KLE cells. We also assessed the effect of visfatin on tumour growth in vivo.. Visfatin stimulated the proliferation of both Ishikawa and KLE cells, and visfatin treatment promoted G1/S phase progression and inhibited endometrial carcinoma cell apoptosis. Visfatin promoted endometrial carcinoma tumour growth in BALB/c-nu mice. Transplanted tumour tissues from an endometrial carcinoma mouse model were analysed using immunohistochemical staining, which revealed much stronger positive signals for Ki-67 with over-abundant visfatin. Western blot analysis revealed that insulin receptor (IR), insulin receptor substrate (IRS)1/2 and key components of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)1/2 signalling pathways were highly expressed in endometrial carcinoma cells exposed to visfatin. Treated cells showed increased C-MYC and cyclin D1 and reduced caspase-3 expression. The effects of visfatin on proliferation and apoptosis were abrogated by treatment with the PI3K inhibitor LY294002 and MEK inhibitor U0126.. Visfatin promotes the malignant progression of endometrial carcinoma via activation of IR and PI3K/Akt and MAPK/ERK signalling. Visfatin may serve as a therapeutic target in the treatment of endometrial carcinoma.

Topics: Acrylamides; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Endometrial Neoplasms; Extracellular Signal-Regulated MAP Kinases; Female; Humans; MAP Kinase Signaling System; Mice; Nicotinamide Phosphoribosyltransferase; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Proto-Oncogene Proteins c-akt; Signal Transduction

The aim of the present study was to investigate the effect of non-steroidal, pure antiestrogenic benzopyran derivative i.e., 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran (K-1) on the growth of human endometrial cancer cells in vivo and in vitro and to elucidate its mechanism of action.. Cell proliferation was assayed by measuring the incorporation of 5'-bromo-2'-deoxyuridine in Ishikawa and primary endometrial cancer cells. The expression of proliferation and apoptotic markers was analyzed by immunoblotting. The effect of K-1 on GPR30-regulated proteins was analyzed by ELISA and by immunoblotting. Nude mice bearing subcutaneous implanted-Ishikawa tumors, were treated for 14days with K-1 (200μg/kg body weight/day/orally). The proliferation markers, GPR30-regulated proteins and apoptotic markers were analyzed by immunoblotting in tumor xenograft. The apoptotic effect of compound K-1 was determined by TUNEL assay.. Compound K-1 inhibited proliferation of endometrial adenocarcinoma cells and decreased the expression of proliferation markers. It caused apoptosis by increasing the expression of apoptotic markers (NOXA, PUMAα) and reducing the expression of p-CREB and BclxL. Compound interfered with GPR30-regulated-EGFR activation, decreased p-ERK, p-c-jun, c-fos, cyclinD1 and c-myc expression. Treatment of tumor-bearing mice with K-1 resulted in a significant decrease in tumor volume and weight. Decreased expression of p-ERK and its downstream molecules and increased expression of apoptotic markers were observed in tumor in K-1 treated animals.. Findings suggest the potent inhibitory effect of compound K-1 on endometrial cancer cellular growth (in-vitro) and on tumor size (in-vivo) which is mediated at least, in part, by interference with GPR30-signaling.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents, Hormonal; Apoptosis; Benzopyrans; Biomarkers, Tumor; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Drug Administration Schedule; Endometrial Neoplasms; Enzyme-Linked Immunosorbent Assay; ErbB Receptors; Female; Humans; In Situ Nick-End Labeling; Mice; Mice, Nude; Piperidines; Receptors, Estrogen; Receptors, G-Protein-Coupled; Treatment Outcome; Tumor Burden

The present study was undertaken to explore the mechanism of anti-proliferative action of benzopyran compound D1 (2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzopyran) and its hydroxy-(D2) and methoxy-(D3) derivatives in Ishikawa and human primary endometrial adenocarcinoma cells.. Transcriptional activation assays were performed using luciferase reporter system and cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The stage of cell cycle was determined by flow-cytometry and real time analysis of cyclinE1 and cdc2 genes. The apoptotic effects were measured by AnnexinV/PI staining and TUNEL. The expression of PCNA, cyclinD1, pAkt, XIAP, cleaved caspase-9, -3, PARP, Bax and Bcl2 were determined by immunoblotting. The caspase-3 activity and mitochondrial membrane potential were measured by colorimetric assay.. All three compounds inhibited E(2)-induced ERE- and AP-1-mediated transactivation and proliferation in endometrial adenocarcinoma cells dose-dependently. Compound D1 caused the arrest of cells in the G(2) phase while D2 and D3 caused arrest in G(1) phase of the cell cycle. All compounds interfered with Akt activation, decreased XIAP expression leading to an increased cleavage of caspase-9, -3, PARP, increased Bax/Bcl2 ratio and caspase-3 activity.. Findings suggest that benzopyran derivatives inhibit cellular proliferation via modulating ER-dependent classical and non-classical signaling mechanisms, interfere with Akt activation and induce apoptosis via intrinsic pathway in endometrial adenocarcinoma cells.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Benzopyrans; CDC2 Protein Kinase; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Cyclin B; Cyclin D1; Cyclin E; Cyclin-Dependent Kinases; Drug Screening Assays, Antitumor; Endometrial Neoplasms; Enzyme Activation; Estradiol; Female; Humans; Oncogene Proteins; Piperidines; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-akt; Receptors, Estrogen; Receptors, Progesterone; Signal Transduction; Transcriptional Activation

Trials with tamoxifen have clearly shown that the risk of developing oestrogen receptor-positive breast cancer can be reduced by at least 50 % with prophylactic agents. The current challenge is to find new agents which achieve this or better efficacy, but with fewer side effects. Recent results indicate that the selective estrogen-receptor modulator (SERM) raloxifene has fewer endometrial cancers, gynaecologic symptoms, and thromboembolic side effects, but is also slightly less efficacious. Results for contralateral tumours in adjuvant trials suggest that aromatase inhibitors may be able to prevent up to 70-80 % of ER-positive breast cancers, and the MAP3 trial has shown to reduce all invasive breast cancer by 65 % in the preventive setting. The IBIS-II trial is currently investigating anastrozole in healthy postmenopausal women. New agents are needed for receptor negative breast cancer and premenopausal women, and several possibilities are currently under investigation.

Topics: Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Endometrial Neoplasms; Female; Humans; Meta-Analysis as Topic; Middle Aged; Piperidines; Preventive Medicine; Pyrrolidines; Raloxifene Hydrochloride; Receptor, ErbB-2; Selective Estrogen Receptor Modulators; Tamoxifen; Tetrahydronaphthalenes; Thiophenes

Increased levels of endogenous and/or exogenous estrogens are one of the well known risk factors of endometrial cancer. Diacylglycerol kinases (DGKs) are a family of enzymes which phosphorylate diacylglycerol (DAG) to produce phosphatidic acid (PA), thus turning off and on DAG-mediated and PA-mediated signaling pathways, respectively. DGK α activity is stimulated by growth factors and oncogenes and is required for chemotactic, proliferative, and angiogenic signaling in vitro. Herein, using either specific siRNAs or the pharmacological inhibitor R59949, we demonstrate that DGK α activity is required for 17-β-estradiol (E2)-induced proliferation, motility, and anchorage-independent growth of Hec-1A endometrial cancer cell line. Impairment of DGK α activity also influences basal cell proliferation and growth in soft agar of Hec-1A, while it has no effects on basal cell motility. Moreover, we show that DGK α activity induced by E2, as well as its observed effects, are mediated by the G protein-coupled estrogen receptor GPR30 (GPER). These findings suggest that DGK α may be a potential target in endometrial cancer therapy.

Topics: Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Endometrial Neoplasms; Enzyme Activation; Enzyme Assays; Estradiol; Female; Gene Knockdown Techniques; Humans; Lipoprotein Lipase; Piperidines; Quinazolinones; Receptors, Estrogen; Receptors, G-Protein-Coupled; RNA Interference

Since estrogens have vital functions in the uterus but might also contribute to endometrial cancer, we sought to determine the in vitro effects of methyl-piperidino-pyrazole (MPP), raloxifene, and beta-estradiol on Ishikawa and RL-95 endometrial cancer, and ovine luminal endometrial (oLE) cell lines and the in vivo effects of these compounds in the rodent uterus. MPP and raloxifene (1 nM) induced significant apoptosis in the endometrial cancer and oLE cell lines compared to beta-estradiol treated and control cells (P

Topics: Animals; Apoptosis; Body Weight; Cell Line, Tumor; Endometrial Neoplasms; Endometrium; Estrogen Receptor alpha; Estrogen Receptor beta; Female; In Situ Nick-End Labeling; Mice; Mice, Knockout; Organ Size; Piperidines; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Sheep; Uterus

Tamoxifen is the primary hormonal therapy for breast cancer and is also used as a breast cancer chemopreventative agent. A major problem with tamoxifen therapy is undesirable endometrial proliferation. To identify proteins associated with the growth stimulatory effects of tamoxifen in an ER-positive model, the present study profiled total cellular and secreted proteins regulated by estradiol and selective estrogen receptor modifiers (SERMs) in the Ishikawa endometrial adenocarcinoma cell line using two-dimensional gel electrophoresis. Following 24 h incubation with 10(-8) M estradiol, 10(-7) M 4-hydroxytamoxifen, or 10(-7) M EM-652 (Acolbifene), nine proteins exhibited significant increase in expression. The proteins identified were heat shock protein 90-alpha, and -beta, heterogeneous nuclear ribonucleoprotein F, RNA polymerase II-mediating protein, cytoskeletal keratin 8, cytoskeletal keratin 18, ubiquitin-conjugating enzyme E2-18 kDa and nucleoside diphosphate kinase B. These protein profiles may serve as novel indices of SERM response and may also provide insight into novel mechanisms of SERM-mediated growth.

Topics: Biomarkers; Carrier Proteins; Cell Line, Tumor; Cell Proliferation; Endometrial Neoplasms; Estradiol; Female; Heterogeneous-Nuclear Ribonucleoprotein Group F-H; HSP90 Heat-Shock Proteins; Humans; Keratins; Lactoferrin; Neoplasm Proteins; Phosphoproteins; Piperidines; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen; Ubiquitin-Conjugating Enzymes

Arzoxifene (Arzox) is a novel benzothiophene analogue with selective estrogen receptor modulator activity similar to raloxifene. Arzox is being developed as a treatment for breast cancer and has a predominantly antiestrogenic effect on the rodent uterus. Our objectives were to verify whether the novel selective estrogen receptor modulator, Arzox, can be a good first-line agent and also be effective at controlling the growth of endometrial cancer after exposure to tamoxifen (Tam).. We compared the effects of Tam and Arzox on the growth of estrogen responsive ECC-1 endometrial cancer cells in vitro, and we determined their antitumor effects on ECC-1 and EnCa101 endometrial carcinoma growth in athymic mice.. We observed that estrogen receptor protein expression is down-regulated by Arzox to the same extent as raloxifene, whereas 4-hydroxytamoxifen, the active metabolite of Tam, does not affect estrogen receptor protein levels. Tam and Arzox inhibit the growth of Tam-naïve ECC-1 tumors in athymic mice. However when Tam-stimulated or estrogen-stimulated (which had been treated with Tam previously) EnCa101 endometrial tumors were treated with Tam or Arzox, we observed a stimulatory effect of both compounds in these models.. The results indicate that Arzox may be a good first-line agent, but it may be ineffective at controlling the growth of endometrial cancer after exposure to Tam. Our data suggest that Arzox stimulates endometrial tumor growth to at least the same extent as Tam, thereby suggesting a limited role as a second-line agent for the patient on Tam who develops occult endometrial cancer.

Topics: Animals; Cell Division; Down-Regulation; Endometrial Neoplasms; Estrogen Antagonists; Female; Humans; Mice; Mice, Nude; Piperidines; Receptors, Estrogen; Tamoxifen; Thiophenes; Transplantation, Heterologous; Tumor Cells, Cultured

Topics: Adult; Breast Neoplasms; Cerebrovascular Disorders; Drug Costs; Endometrial Neoplasms; Estrogen Antagonists; Estrogens; Female; Fractures, Bone; Humans; Middle Aged; Myocardial Infarction; Osteoporosis, Postmenopausal; Piperidines; Placebos; Pulmonary Embolism; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Tamoxifen; Thrombophlebitis

Topics: Breast Neoplasms; Coronary Disease; Endometrial Neoplasms; Estrogen Antagonists; Estrogens; Female; Humans; Molecular Structure; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Raloxifene Hydrochloride; Receptors, Estrogen; Structure-Activity Relationship; Tamoxifen

Although temporary benefits of tamoxifen therapy are observed in up to 40% of women with breast cancer, this compound, which is known to possess mixed estrogenic and antiestrogenic activities, has been associated with increased risk of endometrial carcinoma. This study compares the effects of the novel nonsteroidal pure antiestrogen EM-800 and related compounds with those of a series of antiestrogens on the estrogen-sensitive alkaline phosphatase (AP) activity in human endometrial adenocarcinoma Ishikawa cells. Exposure to increasing concentrations of up to 1000 nM EM-800 or its active metabolite EM-652 alone failed to affect basal AP activity. In contrast, incubation with 10 nM (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, droloxifene, or raloxifene increased the value of this estrogen-sensitive parameter by 3.3-, 3.5-, 2.2-, and 1.6-fold, respectively, a stimulatory effect that was completely reversed by simultaneous exposure to 30 nM EM-800. Moreover, the stimulation of AP activity induced by 1 nM 17beta-estradiol was completely reversed by EM-800, EM-652, or ICI-182780, at the IC50 value of 1.98 +/- 0.23, 1.01 +/- 0.16, and 5.64 +/- 0.59 nM, respectively, whereas the partial blockade exerted by (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, or raloxifene was observed at IC50 values of 13.5 +/- 3.80, 41.0 +/- 7.2, and 3.74 +/- 0.43 nM, respectively. Thus, as assessed by their activity in the human Ishikawa endometrial carcinoma cells, EM-800 and EM-652 are the most potent known antiestrogens in Ishikawa cells, and, most importantly, they are devoid of the estrogenic activity observed in these human endometrial cancer cells with (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, droloxifene, and raloxifene.

Topics: Adenocarcinoma; Alkaline Phosphatase; Benzopyrans; Endometrial Neoplasms; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Humans; Neoplasm Proteins; Piperidines; Propionates; Raloxifene Hydrochloride; Tamoxifen; Toremifene; Tumor Cells, Cultured

A significant increase in endometrial cancer incidence in tamoxifen-treated breast cancer patients has been reported in many recent studies. The major growth stimulators of endometrial tumors are estrogens, but paradoxically, tamoxifen, a known antiestrogen, also stimulates their growth. The mode of action of estrogen can be partially explained by the modulation of insulin-like growth factor (IGF) autocrine or paracrine action. The purpose of the present study was to examine the involvement of the IGF system in the tamoxifen-stimulated growth of Ishikawa endometrial cancer cells by quantitating the IGF-I receptors and their phosphorylation, as well as membrane associated and secreted IGF-binding proteins (IGFBPs). Tamoxifen did not affect the number or affinity of IGF-I receptors. On the other hand, tamoxifen, similar to estradiol, increased IGF-I-stimulated tyrosine phosphorylation of cellular substrates. In contrast, in MCF-7 mammary cancer cells, tamoxifen reduced IGF-induced tyrosine phosphorylation in the presence of estradiol. The pure antiestrogen LY156758 did not affect Ishikawa basal cell growth but inhibited estradiol- and tamoxifen-induced growth. Growth inhibition by LY156758 of tamoxifen and estradiol-stimulated cells was accompanied by a corresponding inhibition of IGF-stimulated tyrosine phosphorylation. Tamoxifen caused a 3-fold decrease in membrane-associated IGFBPs. Moreover, a reduction in soluble IGFBPs was also observed, making the IGF peptides more available to the receptors. A parallel decrease in IGFBP-3 mRNA was also detected. These experiments suggest that tamoxifen, like estradiol, directly sensitizes endometrial cancer cells to the effects of IGFs that act through the type I receptor. Furthermore, the decrease in IGFBPs and the increase in tyrosine phosphorylation in the presence of tamoxifen provides a molecular mechanism that accounts for the uterotropic effects that are seen with tamoxifen therapy.

Topics: Antineoplastic Agents, Hormonal; Cell Division; Endometrial Neoplasms; Estrogen Antagonists; Female; Humans; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Phosphorylation; Piperidines; Raloxifene Hydrochloride; Receptor, IGF Type 1; Tamoxifen; Tumor Cells, Cultured; Tyrosine