epothilone-a and Adenocarcinoma

Estramustine, an agent with both hormonal and non-hormonal effects in men, is supposed to be effective in treating castration-resistant prostate cancer. However, previous studies have reported conflicting results. We conducted this meta-analysis to evaluate the efficacy and toxicity of additional estramustine to chemotherapy.. Data sources including PubMed, Medline, EMBASE, and Cochrane Controlled Trials Register were searched to identify potentially relevant randomized controlled trials. Prostate specific antigen (PSA) response, overall survival, and grade 3 to 4 toxicity were analyzed.. Seven randomized controlled trials, a total of 839 patients, were enrolled. The pooled odds ratio for PSA response was 3.02 (95% CI=1.69-5.39, P=.0002); the pooled hazard ratio for overall survival was .95 (95% CI=.80-1.14, P=.58); the pooled odds ratio for nausea/vomiting and cardiovascular toxicity were 3.90 (95% CI=1.05-14.45, P=.04) and 2.22 (95% CI=1.15-4.30, P=.02). No significant difference was detected for neutropenia, anemia, thrombocytopenia, diarrhea, fatigue, or neuropathy (P>.05).. According to this meta-analysis, chemotherapy with additional estramustine increased the PSA response rate. However, it increased the risk of grade 3 or 4 adverse effects such as nausea/vomiting and cardiovascular events, and the overall survival was not improved for castration-resistant prostate cancer patients.

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cardiovascular Diseases; Combined Modality Therapy; Docetaxel; Epirubicin; Epothilones; Estramustine; Fatigue; Gastrointestinal Diseases; Hematologic Diseases; Humans; Male; Orchiectomy; Paclitaxel; Peripheral Nervous System Diseases; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Salvage Therapy; Survival Analysis; Taxoids; Treatment Outcome; Vinblastine

The management of metastatic pancreatic adenocarcinoma is a challenge for medical oncologists because of both the aggressive nature of the disease and the relative paucity of effective systemic treatments with activity against this type of tumor. In the effort to discover new agents and combinations that may augment the therapeutic arsenal available for the management of this cancer, early phase clinical trials have been performed using ixabepilone, an epothilone B analog, with promising results. Targeting the microtubule system with certain taxanes in the management of pancreatic adenocarcinoma has been validated; ixabepilone also targets the microtubule system, interfering with it in an alternate manner from the taxane mechanism. Ixabepilone has demonstrated activity in cancers that have become taxane-resistant as well as those that never had any demonstrable taxane susceptibility. The available data for the use of ixabepilone in the management of pancreatic adenocarcinoma are limited but promising. Single-arm studies have demonstrated both clinical efficacy and tolerable toxicity for the use of ixabepilone as monotherapy. The trial data available for ixabepilone used as a part of combination therapy are similar: it has been paired with chemotherapy (carboplatin, irinotecan) and biologic therapy (dasatinib, sunitinib) at the Phase I level to treat solid tumors in general, again with tolerable side effects and a suggestion of benefit. A single Phase II study has evaluated combination therapy with ixabepilone in the management of patients with pancreatic cancer, pairing it with cetuximab with clinical benefit. Although these trials are promising with regard to addition of ixabepilone to the slim armamentarium for management of pancreatic cancer, further work is still to be done. Importantly, this work bears the burden of not only validating the clinical benefit of ixabepilone, but also of determining whether this benefit is enhanced in any way by combination therapy, and where ixabepilone fits in the sequence of management for patients with metastatic pancreatic cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Epothilones; Humans; Neoplasm Metastasis; Pancreatic Neoplasms; Tubulin Modulators

Review the recent advances in the treatment of androgen independent prostate cancer (AIPC).. Review recent abstracts and literature utilizing Medline/PubMed using key words: androgen independent/hormone refractory prostate cancer, novel treatment options, Phase II, III trials and meeting abstracts/presentations.. Two pivotal trials SWOG (Southwest Oncology Group) study 9916 and Taxotere 327 have shown that survival can be improved in this population by administration of chemotherapy with docetaxel every three weeks intravenously. An overall survival of 19 months could be achieved with docetaxel/prednisone compared to 16 months with mitoxantrone/prednisone. Despite this, there is a need to improve on this survival benefit because the relapse free survival among responders is often short (6 months) and patients often would have progression of their cancer leading to death. Satraplatin, a novel platinum analogue had been found to provide an additional 1.5 week progression free survival benefit in this population in the second line setting. There is however, a need to develop less toxic drugs that would improve survival significantly.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Atrasentan; Benzamides; Benzenesulfonates; Bevacizumab; Calcitriol; Cancer Vaccines; Docetaxel; Drug Screening Assays, Antitumor; Epothilones; Forecasting; Humans; Imatinib Mesylate; Male; Niacinamide; Phenylurea Compounds; Piperazines; Prostatic Neoplasms; Pyridines; Pyrimidines; Pyrrolidines; Randomized Controlled Trials as Topic; Salvage Therapy; Sorafenib; Taxoids; Thionucleotides

Despite high initial sensitivity to chemotherapy, TNBC is associated with a poor prognosis, highlighting the need for novel therapeutic strategies. The aim of this multicenter, randomized, open-label phase II trial was to assess the efficacy of ixabepilone as monotherapy, and the combination of ixabepilone with cetuximab, as first-line treatment in patients with triple-negative locally advanced nonresectable and/or metastatic breast cancer.. Women were randomly assigned to receive either ixabepilone (40 mg/m(2)) every 21 days (n = 40), or ixabepilone (40 mg/m(2)) every 21 days with cetuximab (400 mg/m(2) loading dose, followed by 250 mg/m(2)) once weekly (n = 39). The primary end point of the trial was to estimate the response rates of ixabepilone monotherapy and ixabepilone with cetuximab combination therapy.. Of 79 randomized patients, 77 were treated. Based on an intent-to-treat analysis, an objective response rate of 30% (95% confidence interval [CI], 16.6-46.5) was observed in the monotherapy arm, and 35.9% (95% CI, 21.2-52.8) in the combination arm. Median progression-free survival was 4.1 months in both treatment groups. Safety findings were consistent with the known individual toxicity profiles of ixabepilone and cetuximab. Skin and subcutaneous tissue disorders were more common with combination therapy, as were discontinuations because of adverse events.. Ixabepilone monotherapy and the ixabepilone and cetuximab combination demonstrated similar levels of clinical activity in first-line treatment of advanced TNBC, with a predictable safety profile. Further investigation of novel therapies for TNBC is required to improve patient outcomes.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Disease Progression; Disease-Free Survival; Epothilones; Female; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Treatment Outcome; Triple Negative Breast Neoplasms

Ixabepilone is a member of the epothilone class of antineoplastic agents with activity against taxane-resistant tumors, and low susceptibility to common mechanisms of tumor resistance. This study evaluated ixabepilone in lieu of a taxane in combination with carboplatin and trastuzumab as neoadjuvant treatment for operable HER2-positive breast cancer.. Patients ≥ 18 years of age with histologically-confirmed HER2-positive adenocarcinoma of the breast (clinical T1-T3, N0-N2, M0), normal left ventricular ejection fraction, and adequate organ function received trastuzumab 6 mg/kg intravenous (I.V.) (with 8 mg/kg loading dose cycle 1), ixabepilone 40 mg/m(2) I.V., and carboplatin area under the curve = 6.0 I.V. on day 1 of each 21-day cycle. Prophylactic growth factor support was permitted. After completing 6 cycles, patients underwent definitive surgery. After surgery, patients continued trastuzumab every 3 weeks for a total of 1 year. Locoregional radiation therapy and endocrine therapy was administered per institutional guidelines. The primary end point was the rate of pCR.. Fifty-eight eligible women (median tumor size, 3.0 cm; clinical axillary lymph node involvement, 67%) initiated treatment between April 2009 and February 2010. Fifty-two patients (90%) underwent surgery, and pCR was observed in 27 patients (52%). Grade 3/4 neutropenia was the most common toxicity, occurring in 69% of patients and complicated by fever in 4 patients.. The combination of ixabepilone, carboplatin, and trastuzumab was feasible and active as a neoadjuvant regimen. Although the pCR rate of 52% falls within the range reported with other taxane/trastuzumab-based regimens, the greater incidence of severe neutropenia is a disadvantage for this regimen.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Chemotherapy, Adjuvant; Epothilones; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoadjuvant Therapy; Receptor, ErbB-2; Trastuzumab

Ixabepilone is an epothilone B analogue with activity in a variety of solid malignancies, including prostate cancer. The main dose-limiting toxicity of ixabepilone is myelosuppression when administered by using an every 3-week schedule. Here we evaluate the activity of a weekly ixabepilone in men with metastatic castrate-resistant prostate cancer to minimize hematologic toxicity.. BMS-247550 (ixabepilone) is an epothilone B analogue with activity in taxane-resistant cancer cell lines. Here we report the activity and toxicity of ixabepilone, administered by using a weekly schedule, in men with metastatic castrate-resistant prostate cancer (CRPC).. Patients with metastatic CRPC received ixabepilone at 20 mg/m(2) intravenous weekly x 3, in 4-week cycles. This noncomparative study stratified patients to either a chemotherapy naive (CN), prior taxane (Tax) only, or 2 prior cytotoxic (TCx) chemotherapy arm. The primary endpoint was prostate-specific antigen response by using PCWG (Prostate Cancer Working Group) 1 criteria. Secondary endpoints included radiographic response when using RECIST (Response Evaluation Criteria In Solid Tumors).. In total, 124 patients were enrolled, of whom, 109 were eligible (35 CN, 42 Tax, and 32 TCx) for the primary response determination in this study. Prostate-specific antigen responses were seen in 12 (34.3%) of 35, 12 (28.6%) of 42, and 7 (21.9%) of 32 patients with the partial objective response in 5 (22.7%) of 22, 2 (8.0%) of 25, and 0 (0.0%) of 24 patients for the CN, Tax, and TCx arms, respectively. Significant (grade 3/4) neutropenia was seen in 6 (15.4%), 7 (14.6%), and 9 (25.0%); and grade 3/4 sensory neuropathy was seen in 8 (20.5%), 12 (25.0%), and 12 (33.3%) for CN, Tax, and TCx, respectively. Grade 3/4 thrombocytopenia was infrequent and seen in only one patient on the CN and the TCx arm.. Ixabepilone was found to have an acceptable toxicity profile when administered by using a weekly schedule with less myelosuppression compared with prior studies when using the every 3-week schedule. Single-agent activity was observed and met prespecified activity levels for the Tax treated arm.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents; Bone Neoplasms; Castration; Disease-Free Survival; Epothilones; Humans; Kaplan-Meier Estimate; Lymphatic Metastasis; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

Ixabepilone is a semisynthetic epothilone B analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. We carried out a phase I trial of ixabepilone plus pegylated liposomal doxorubicin (PLD) in patients with advanced taxane-pretreated ovarian and breast cancer.. Patients with recurrent ovarian or breast carcinoma received PLD every 3 or 4 weeks plus five different dose schemas of ixabepilone in cohorts of three to six patients.. Thirty patients received a total of 142 treatment cycles of the PLD-ixabepilone combination. The recommended phase II dose and schedule of ixabepilone was 16 mg/m(2) on days 1, 8, and 15 plus PLD 30 mg/m(2) given on day 1, repeated every 4 weeks. Hand-foot syndrome and mucositis were dose limiting when both ixabepilone and PLD were given every 3 or 4 weeks. Objective responses were observed in 3 of 13 patients (23%) with breast cancer and 5 of 17 patients (29%) with ovarian cancer.. Ixabepilone may be safely combined with PLD, but tolerability is highly dependent upon the scheduling of both agents. This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Doxorubicin; Epothilones; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Polyethylene Glycols; Survival Rate; Taxoids; Treatment Outcome

This phase II study evaluated the efficacy and safety of ixabepilone as neoadjuvant therapy for invasive breast cancer not amenable to breast conservation surgery. Gene expression studies were undertaken using genes that were identified as potentially associated with sensitivity/resistance to ixabepilone in prior preclinical investigations.. Patients with invasive breast cancer >or= 3 cm were eligible. Ixabepilone 40 mg/m(2) was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle for four or fewer cycles.. One hundred sixty-one patients were treated. The overall complete pathologic response (pCR) rate was 18% in breast and 29% in estrogen receptor (ER) -negative patients. Gene expression data were available for 134 patients. ER gene expression (ER1) was inversely related to pCR in breast and had a positive predictive value (PPV) of 37% and negative predictive value (NPV) of 92%. A 10-gene penalized logistic regression (PLR) model developed from 200 genes predictive of ixabepilone sensitivity in preclinical experiments included ER and tau and had higher PPV (45%) and comparable NPV (89%) to ER1. Grade 3 to 4 adverse events (AEs) were reported for 32% of patients. Except for neutropenia and leukopenia, all grade 3 to 4 AEs occurred in

Topics: Adenocarcinoma; Antineoplastic Agents; Breast Neoplasms; Drug Resistance, Neoplasm; Epothilones; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lymph Nodes; Neoadjuvant Therapy; Predictive Value of Tests; Receptors, Estrogen; RNA, Messenger

Ixabepilone (BMS-247550) is a semi-synthetic, microtubule stabilizing epothilone B analogue which is more potent than taxanes and has displayed activity in taxane-resistant patients. The human plasma pharmacokinetics of ixabepilone have been described. However, the excretory pathways and contribution of metabolism to ixabepilone elimination have not been determined. To investigate the elimination pathways of ixabepilone we initiated a mass balance study in cancer patients. Due to autoradiolysis, ixabepilone proved to be very unstable when labeled with conventional [14C]-levels (100 microCi in a typical human radio-tracer study). This necessitated the use of much lower levels of [14C]-labeling and an ultra-sensitive detection method, Accelerator Mass Spectrometry (AMS). Eight patients with advanced cancer (3 males, 5 females; median age 54.5 y; performance status 0-2) received an intravenous dose of 70 mg, 80 nCi of [14C]ixabepilone over 3 h. Plasma, urine and faeces were collected up to 7 days after administration and total radioactivity (TRA) was determined using AMS. Ixabepilone in plasma and urine was quantitated using a validated LC-MS/MS method. Mean recovery of ixabepilone-derived radioactivity was 77.3% of dose. Fecal excretion was 52.2% and urinary excretion was 25.1%. Only a minor part of TRA is accounted for by unchanged ixabepilone in both plasma and urine, which indicates that metabolism is a major elimination mechanism for this drug. Future studies should focus on structural elucidation of ixabepilone metabolites and characterization of their activities.

Topics: Adenocarcinoma; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Chromatography, Liquid; Colonic Neoplasms; Epothilones; Feces; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Sigmoid Neoplasms; Tandem Mass Spectrometry

This randomized, noncomparative, multicenter, clinical trial evaluated ixabepilone or mitoxantrone/prednisone (MP) as second-line chemotherapy for taxane-refractory, hormone-refractory, prostate cancer (HRPC).. Patients with HRPC that progressed during or within 60 days of cessation of taxane chemotherapy were randomly selected with equal probability to ixabepilone 35 mg/m(2) intravenously every 3 weeks, or mitoxantrone 14 mg/m(2) intravenously every 3 weeks and prednisone 5 mg orally twice daily. Treatment continued until progression or toxicity; crossover was allowed.. Forty-one patients were accrued to each arm of the study. The median number of cycles administered for each arm was 3. Median survival from protocol entry was 10.4 months with ixabepilone and 9.8 months with MP. Prostate-specific antigen (PSA) declines of >or=50% were observed in 17% of ixabepilone (95% CI, 7-32) and 20% of second-line MP patients (95% CI, 9-35). Partial responses were observed in 1 of 24 ixabepilone and in 2 of 21 MP patients with evaluable measurable disease. Median duration of second-line ixabepilone and MP treatment was 2.2 months and 2.3 months, respectively. For third-line crossover treatment, PSA declines of >or=50% were observed in 3 of 27 ixabepilone-treated and 4 of 15 MP-treated patients. Prior taxane response was associated with an increased likelihood of second-line ixabepilone or MP response. Low baseline lactate dehydrogenase and absence of visceral metastases independently predicted improved survival. The most common grade 3/4 toxicity associated with second-line treatment was neutropenia (54% of ixabepilone patients and 63% of MP patients).. Ixabepilone and MP had modest activity as second-line chemotherapy for docetaxel-refractory HRPC. The median survival for the entire cohort treated in this study was 9.8 months.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cross-Over Studies; Docetaxel; Drug Resistance, Neoplasm; Epothilones; Humans; Male; Middle Aged; Mitoxantrone; Neoplasms, Hormone-Dependent; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Salvage Therapy; Survival Rate; Taxoids; Treatment Outcome

Ixabepilone is one of the epothilones, a new class of cytotoxics, that function as microtubule-stabilizing agents. With the primary endpoint of assessing ixabepilone's response rate against metastatic gastric cancer previously treated with a taxane, we performed a multi-center phase II trial.. Patients with histologically documented metastatic gastric or gastroesophageal adenocarcinoma, who had previously received a taxane, were eligible. Patients were required to have near normal organ function, > or =18 years of age, ECOG performance status of 0 or 1. A written informed consent was obtained from all patients. Ixabepilone was administered over one hour intravenously at a dose of 50 mg/m2 every 21 days (23 patients; cohort A) and 24 subsequent patients were treated with an amended protocol schedule to receive 6 mg/m2 intravenously on days 1-5 every 21 days (cohort B).. A total of 47 patients were treated. Most patients were men with a median performance status of 1. Two of 23 patients in cohort A achieved a confirmed partial response (9%, 95% CI 1.1-28%) but none of the 24 patients in cohort B achieved a response. A higher proportion of patients in cohort A experienced Grade 3/4 toxicities compared with those in cohort B.. Ixabepilone, on a once every 21-day schedule, is modestly active against metastatic gastric cancer previously treated with a taxane. The days 1-5 every 21 days schedule had a more favorable safety profile but no activity. The results of this study suggest that once every 21-day ixabepilone schedule should be pursued further in untreated gastric or gastroesophageal adenocarcinoma patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Bridged-Ring Compounds; Disease Progression; Epothilones; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Peripheral Nervous System Diseases; Stomach Neoplasms; Taxoids

The purpose of this Phase II multi-institutional study was to define the efficacy and toxicity of ixabepilone in patients with advance pancreatic adenocarcinoma.. Patients were required to have pancreatic adenocarcinoma and metastatic or recurrent disease that was not amenable to curative resection. Performance status was 0-1, and patients could not have had prior chemotherapy, or chemoradiation therapy for their advanced disease although prior local palliative radiation was allowed. Ixabepilone was administered iv as a 3 hour infusion every 21 days. Initially, the dose was 50 mg/m(2) but this was lowered to 40 mg/m(2) shortly after the trial opened because of concerns about neurotoxicity.. Sixty-two patients were registered however 2 were ineligible because they did not have recurrent or metastatic disease. For the 60 eligible patients, 22 had performance status of 0 and 38 performance status of 1. The estimated 6-month survival was 60% (95% CI 48%-72%) with a median survival of 7.2 months and an estimated time to treatment failure of 2.3 months. Out of 56 patients with measurable disease there were 5 confirmed partial responses for a confirmed response probability of 9% (95% CI 3%-20%) and 7 unconfirmed partial responses for an overall response probability of 21% (95% CI 12%-34%). Common toxicities were neutropenia/granulocytopenia, nausea and vomiting and neuropathy. There was one death, cause not determined but judged "possibly" related to treatment.. Ixabepilone shows encouraging activity in patients with advanced pancreatic cancer and should be investigated further in this disease.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Epothilones; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome; Tubulin Modulators

The epothilones are a new class of tubulin-polymerizing agents with activity in taxane-sensitive and resistant tumor models. We evaluated ixabepilone (BMS-247550) in patients with metastatic hormone-refractory prostate cancer (HRPC).. Eligible patients had chemotherapy-naive metastatic HRPC, a Zubrod performance status of 0 to 2, and adequate organ function. All patients received BMS-247550 at 40 mg/m2 over 3 hours every 3 weeks. The primary end point was proportion of patients achieving a prostate-specific antigen (PSA) response.. Forty-eight patients with metastatic HRPC were registered. Forty-two patients were eligible, with a median age of 73 years and a median PSA level of 111 ng/mL; 78% had bone-only or bone and soft tissue metastases, and 88% had objective radiologic disease progression at registration. Grade 3 and 4 adverse events (AEs) occurred in 16 and three patients, respectively. All grade 4 toxicities were neutropenia or leukopenia. The most frequent grade 3 AEs were neuropathy (eight patients), hematologic toxicity (seven patients), flu-like symptoms, and infection (five patients each). There were no grade 3/4 thrombocytopenia or grade 5 AEs. There were 14 confirmed PSA responses (33%; 95% CI, 20% to 50%); 72% of PSA responders had declines greater than 80%, and two patients achieved an undetectable PSA. The estimated median progression-free survival is 6 months (95% CI, 4 to 8 months), and the median survival is 18 months (95% CI, 13 to 24 months).. Ixabepilone has demonstrated activity in patients with chemotherapy-naive metastatic HRPC. Major toxicities were neutropenia and neuropathy. Further testing to define its activity relative to standard therapy is warranted.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Bone Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Epothilones; Follow-Up Studies; Hematologic Diseases; Humans; Male; Middle Aged; Nervous System Diseases; Prostate-Specific Antigen; Prostatic Neoplasms; Soft Tissue Neoplasms; Treatment Outcome

Several trials have demonstrated that the response proportions to microtubule agents in patients with prostate cancer are increased by the addition of estramustine phosphate (EMP). The epothilone B analog BMS-247550 is a novel microtubule agent that has shown activity in taxane-resistant tumors. We conducted a dose-escalation study to determine a safe dose of BMS-247550 to combine with EMP in patients with metastatic prostate cancer.. Chemotherapy-naive patients with castrate-metastatic prostate cancer were treated with intravenous BMS-247550 and oral EMP (280 mg three times daily for 5 days) every 3 weeks.. Thirteen patients were treated at two dose levels (35 and 40 mg/m(2)). Three of six patients treated at 40 mg/m(2) developed grade 4 neutropenia, establishing 35 mg/m(2) as the maximum-tolerated dose. Significant peripheral neuropathy (grade >/= 2) was related to dose level and infusion rate. A decline in prostate-specific antigen (PSA) of >/= 50% was seen in 11 of 12 evaluable patients (92%) (95% confidence interval 76% to 100%). There were objective responses in soft tissue (57%) and bone metastasis (40%).. The phase II dose of BMS-247550 combined with EMP is 35 mg/m(2) over 3 h every 3 weeks. This combination is safe and >/= 50% post-therapy declines in PSA were seen in 11 of 12 patients (92%).

Topics: Adenocarcinoma; Adult; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Bone Neoplasms; Castration; Dose-Response Relationship, Drug; Epothilones; Estramustine; Humans; Male; Maximum Tolerated Dose; Microtubules; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

Pancreatic adenocarcinoma (PAAD) is one of the most common malignant tumors of the digestive tract. Pyroptosis is a newly discovered programmed cell death that highly correlated with the prognosis of tumors. However, the prognostic value of pyroptosis in PAAD remains unclear.. A total of 178 pancreatic cancer PAAD samples and 167 normal samples were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The "DESeq2" R package was used to identify differntially expressed pyroptosis-related genes between normal pancreatic samples and PAAD samples. The prognostic model was established in TCGA cohort based on univariate Cox and the least absolute shrinkage and selection operator (LASSO) Cox regression analyses, which was validated in test set from Gene Expression Omnibus (GEO) cohort. Univariate independent prognostic analysis and multivariate independent prognostic analysis were used to determine whether the risk score can be used as an independent prognostic factor to predict the clinicopathological features of PAAD patients. A nomogram was used to predict the survival probability of PAAD patients, which could help in clinical decision-making. The R package "pRRophetic" was applied to calculate the drug sensitivity of each samples from high- and low-risk group. Tumor immune infiltration was investigated using an ESTIMATE algorithm. Finally, the pro-tumor phenotype of GSDMC was explored in PANC-1 and CFPAC-1 cells.. On the basis of univariate Cox and LASSO regression analyses, we constructed a risk model with identified five pyroptosis-related genes (IL18, CASP4, NLRP1, GSDMC, and NLRP2), which was validated in the test set. The PAAD samples were divided into high-risk and low-risk groups on the basis of the risk score's median. According to Kaplan Meier curve analysis, samples from high-risk groups had worse outcomes than those from low-risk groups. The time-dependent receiver operating characteristics (ROC) analysis revealed that the risk model could predict the prognosis of PAAD accurately. A nomogram accompanied by calibration curves was presented for predicting 1-, 2-, and 3-year survival in PAAD patients. More importantly, 4 small molecular compounds (A.443654, PD.173074, Epothilone. B, Lapatinib) were identified, which might be potential drugs for the treatment of PAAD patients. Finally, the depletion of GSDMC inhibits the proliferation, invasion, and migration of pancreatic adenocarcinoma cells.. In this study, we developed a pyroptosis-related prognostic model based on IL18, CASP4, NLRP1, NLRP2, and GSDMC , which may be helpful for clinicians to make clinical decisions for PAAD patients and provide valuable insights for individualized treatment. Our result suggest that GSDMC may promote the proliferation and migration of PAAD cell lines. These findings may provide new insights into the roles of pyroptosis-related genes in PAAD, and offer  new therapeutic targets for the treatment of PAAD.

Topics: Adenocarcinoma; Biomarkers, Tumor; DNA-Binding Proteins; Epothilones; Gene Expression Regulation, Neoplastic; Humans; Interleukin-18; Lapatinib; Pancreatic Neoplasms; Pore Forming Cytotoxic Proteins; Prognosis; Pyroptosis

High mortality rates in ovarian and liver cancer are largely a result of resistance to currently used chemotherapy. Here, we investigated genotoxic and pro-oxidant effects of metformin (MET) and epothilone A (A) in combination with respect to apoptosis in HepG2 and SKOV-3 cancer cells. Reactive oxygen species (ROS) was studied using 2',7'-dichlorodihydrofluoresein diacetate, and samples were analyzed for the presence and absence of the N-acetylcysteine (NAC). Expression of genes involved in programmed cell death, oxidative and alkylating DNA damage was measured. Probes were analyzed in the presence of Akt or nuclear factor-κB inhibitor. Compared to either drug alone, combination of epothilone A and metformin was more potent; decreased Akt level; and elevated percentage of apoptotic cells, induced cell cycle arrest at G1 phase and elevated the sub-G1 cell population by increasing the mRNA level of caspase-3, poly (ADP-ribose) polymerase-1 and H2AX. The anticancer effect of the drug combination was partially reversed by NAC supplementation, suggesting that ROS generation is required to induce apoptosis. The present study demonstrates that novel combination such as epothilone A and MET show promise in expanding ovarian and liver cancer therapy.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Cell Line, Tumor; DNA Damage; Drug Resistance, Neoplasm; Epothilones; Female; Gene Expression Regulation, Neoplastic; Histones; Humans; Hypoglycemic Agents; Liver Neoplasms; Metformin; Neoplasm Proteins; Ovarian Neoplasms; Oxidative Stress; Poly (ADP-Ribose) Polymerase-1; Proto-Oncogene Proteins c-akt

Gastric cancer is an important health issue worldwide. Currently, improving the therapeutic efficacy of chemotherapy drugs is an important goal of cancer research. Alpha-7 nicotine acetylcholine receptor (A7-nAChR) is the key molecule that mediates gastric cancer progression, metastasis, and therapy responses; however, the role of A7-nAChR in the therapeutic efficacy of ixabepilone remains unclear. A7-nAChR expression was silenced by small interfering RNA (siRNA) technology. The cytotoxicity of ixabepilone was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and ixabepilone-induced apoptosis was analyzed by flow cytometry and annexin V/propidium iodide (PI) apoptotic assay. The expression patterns of anti-apoptotic proteins (AKT, phospho-AKT, Mcl-1, and Bcl-2) and pro-apoptotic proteins (Bad and Bax) were determined by western blot. Our study found that A7-nAChR knockdown (A7-nAChR-KD) AGS cells were more sensitive to ixabepilone administration than scrambled control AGS cells. We found that A7-nAChR knockdown enhanced ixabepilone-induced cell death as evidenced by the increased number of annexin V-positive (apoptotic) cells. After scrambled control and A7-nAChR-KD cells were treated with ixabepilone, we found that pAKT and AKT levels were significantly reduced in both groups of cells. The levels of Bcl-2 and the anti-apoptotic Mcl-1 isoform increased dramatically after ixabepilone treatment in scrambled control cells but not in A7-nAChR-KD cells. Bad and Bax levels did not change between the treatment group and vehicle group in both A7-nAChR-KD and scrambled control cells, whereas cleaved PARP levels dramatically increased in ixabepilone-treated A7-nAChR-KD cells. Our results demonstrated that knockdown of A7-nAChR enhanced the sensitivity of gastric cancer cells to ixabepilone administration. Thus, the A7-nAChR expression level in patients with gastric cancer may be a good indicator of ixabepilone sensitivity.

Topics: Adenocarcinoma; alpha7 Nicotinic Acetylcholine Receptor; Apoptosis; Blotting, Western; Cell Cycle; Cell Proliferation; Drug Resistance, Neoplasm; Epothilones; Flow Cytometry; Humans; RNA, Small Interfering; Stomach Neoplasms; Tubulin Modulators; Tumor Cells, Cultured

Resistance to microtubule-stabilizing agents is a major hurdle for successful cancer therapy. We investigated combined treatment of microtubule-stabilizing agents (MSAs) with inhibitors of angiogenesis to overcome MSA resistance.. Treatment regimens of clinically relevant MSAs (patupilone and paclitaxel) and antiangiogenic agents (everolimus and bevacizumab) were investigated in genetically defined MSA-resistant lung (A549EpoB40) and colon adenocarcinoma (SW480) tumor xenografts in nude mice (CD1-Foxn1, ICRnu; 5-14 per group). Tumor growth delays were calculated by Kaplan-Meier analysis with Holm-Sidak tests. All statistical tests were two-sided.. Inhibition of mTOR-kinase by everolimus only minimally reduced the proliferative activity of β tubulin-mutated lung adenocarcinoma cells alone and in combination with the MSA patupilone, but everolimus inhibited expression and secretion of vascular endothelial growth factor (VEGF) from these cells. mTOR-kinase inhibition strongly sensitized tumor xenografts derived from these otherwise MSA-resistant tumor cells to patupilone. Tumors treated with the combined modality of everolimus and patupilone had statistically significantly reduced tumor volume and stronger tumor growth delay (16.2 ± 1.01 days) than control- (7.7 ± 0.3 days, P = .004), patupilone- (10 ± 0.97 days, P = .009), and everolimus-treated (10.6 ± 1.4 days, P = .014) tumors. A combined treatment modality with bevacizumab also resensitized this MSA-refractory tumor model to patupilone. Treatment combination also strongly reduced microvessel density, corroborating the relevance of VEGF targeting for the known antivasculature-directed potency of MSA alone in MSA-sensitive tumor models. Resensitization to MSAs was also probed in P glycoprotein-overexpressing SW480-derived tumor xenografts. Different bevacizumab regimens also sensitized this otherwise-resistant tumor model to clinically relevant MSA paclitaxel.. A treatment combination of MSAs with antiangiogenic agents is potent to overcome tumor cell-linked MSA resistance and should be considered as strategy for MSA-refractory tumor entities.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Drug Resistance, Neoplasm; Epothilones; Everolimus; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Mice; Mice, Nude; Microtubules; Paclitaxel; Real-Time Polymerase Chain Reaction; RNA, Neoplasm; Sirolimus; TOR Serine-Threonine Kinases; Tubulin Modulators; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Ixabepilone (Ixempra, BMS-247550), a semisynthetic analog of epothilone B, is a microtubule-targeted drug in clinical use for treatment of metastatic or locally advanced breast cancer. Ixabepilone's binding and mechanism of action on microtubules and their dynamics, as well as its interactions with isotypically altered microtubules, both in vitro and in tumor cells, have not been described. Microtubules are dynamic polymers of the protein tubulin that function in mitosis, intracellular transport, cell proliferation, and migration. They continually undergo dynamic instability, periods of slow growth and rapid shortening that are crucial to these cell functions. We determined ixabepilone's microtubule binding and polymerization effects in vitro and also determined its effects on inhibition of dynamic instability in vitro and in cells, both with and without removal of the βIII isotype of tubulin. The βIII isotype of tubulin is associated with drug resistance and tumor aggressivity. We found that removal (in vitro) and knockdown (in cells) of βIII-tubulin led to increased inhibition of microtubule dynamic instability by ixabepilone. Depletion of βIII-tubulin from MCF7 human breast cancer cells also induced increased mitotic arrest by ixabepilone. Thus, βIII-tubulin expression suppresses the antitumor effects of ixabepilone, indicating that increased βIII-tubulin may be an important contributor to the development of resistance to ixabepilone.

Topics: Adenocarcinoma; Amino Acid Sequence; Animals; Antineoplastic Agents; Brain Chemistry; Breast Neoplasms; Cattle; Drug Resistance, Neoplasm; Epothilones; Female; Humans; MCF-7 Cells; Microtubules; Molecular Structure; Paclitaxel; Protein Binding; Protein Isoforms; RNA Interference; RNA, Small Interfering; Structure-Activity Relationship; Transfection; Tubulin; Tubulin Modulators

The use of microtubule stabilizing agents (MSAs) is a promising strategy for anti-cancer therapy alone and as part of combined treatment modalities with ionizing radiation. However MSA-provoked molecular and cellular processes including the regulation of intercellular, paracrine signaling pathways are far from clear. Here we investigated the interference of the novel, clinically relevant MSA patupilone (epothilone B) with the tumor-cell derived vascular endothelial growth factor (VEGF), which is most relevant for tumor angiogenesis. Low-dose, sub-nanomolar concentrations of patupilone specifically reduced hypoxia-driven stabilization of the transcription factor HIF-1α in the patupilone-sensitive lung adenocarcinoma cell line A549, but not in the mutant derivative cell line A549.EpoB40. Patupilone further reduced hypoxia-induced VEGF expression and secretion but only in the A549 wildtype cell line. In the wildtype cell line, ionizing radiation alone induced hypoxia-dependent VEGF-expression but a strong dominant counteracting effect of patupilone was always observed when ionizing radiation was combined with patupilone, on the level of HIF-1α protein stability, VEGF-expression and VEGF-secretion. These results demonstrate that patupilone and ionizing radiation dysregulate hypoxia-induced stress responses, which might contribute to the potency of this promising, combined treatment modality.

Topics: Adenocarcinoma; Cell Line, Tumor; Combined Modality Therapy; Epothilones; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; Neovascularization, Pathologic; Paracrine Communication; Protein Stability; Radiation, Ionizing; Tubulin Modulators; Vascular Endothelial Growth Factor A

The anti-human epidermal growth factor receptor 2 (HER2) agent trastuzumab has improved outcomes in breast cancer patients with HER2 over-expressing tumours. However, systemic treatment for patients with HER2-negative disease is still limited to endocrine and cytotoxic therapies. The increasing use of the anthracyclines and taxanes in early stage disease has reduced the available therapeutic options for patients with relapsed disease, and choices are further limited for patients with triple-negative tumours, who typically have a poor prognosis. The novel agents bevacizumab and ixabepilone were recently approved for metastatic breast cancer, and numerous other agents are currently in clinical development that may contribute further valuable therapeutic options.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cytotoxins; Drug Carriers; Drug Delivery Systems; Drug Resistance, Neoplasm; Epothilones; Estradiol; Female; Fulvestrant; Humans; Intracellular Signaling Peptides and Proteins; Nanoparticles; Neoplasm Proteins; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Salvage Therapy; TOR Serine-Threonine Kinases

To explore the association between progression-free survival and overall survival time in patients with castration-resistant prostate cancer treated with microtubule-targeted therapies.. We retrospectively studied patients treated in three trials evaluating a taxane or an epothilone for progressive castration-resistant prostate cancer. Study subjects were 98 patients with bone metastases; 63 of them also had soft tissue lesions. All scans were reviewed independently. Associations of radiographic progression-free survival and prostate-specific antigen (PSA) progression-free survival with survival time were measured using Kendall's tau, adjusted for right censoring. A smoothing procedure was applied to estimate Kendall's tau within each neighborhood of the follow-up process.. The overall associations between progression-free survival time and overall survival time were moderate: 0.4 for radiographic progression-free survival and 0.33 for PSA progression-free survival. The association between radiographic progression-free survival and overall survival was weakest early in the follow-up process, whereas the PSA association was weakest when the progression-free survival-related event (PSA progression, death, or censoring) occurred after 6 months from the start of treatment.. Current measures of progression-free survival time for men with castration-resistant prostate cancer are not strongly concordant with survival time. Factors that attenuate the association include interval censoring and the discontinuation of therapy early in the follow-up due to imaging changes that may not reflect true failure of the treatment. For radiographic progression-free survival, the association may be increased by requiring confirmation of progression with a second scan, as is routinely done when assessing response.

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Bone Neoplasms; Clinical Trials as Topic; Disease Progression; Disease-Free Survival; Epothilones; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Soft Tissue Neoplasms; Survival Rate; Taxoids

A Taxol-resistant cell line, K20T, which does not express P-glycoprotein, was selected with Taxol from human MDA-MB-231 breast adenocarcinoma cells and maintained in the presence of 20nM Taxol. K20T cells were approximately 18-fold resistant to Taxol, displayed cross-resistance to Taxotere and the epothilones, but little cross-resistance to discodermolide. Sequence analysis of the class I beta-tubulin indicated that it harbored an A593G mutation resulting in a change from glutamate to glycine at amino acid 198, which is near the intradimer interface within the alpha/beta-tubulin heterodimer. An HA-tagged wild-type class I beta-tubulin expression vector was transfected into the K20T cells. Immunofluorescence studies demonstrated that this exogenous tubulin was incorporated into cellular microtubules and Western blot analysis indicated that the K20T transfectants predominantly expressed the exogenous wild-type class I beta-tubulin. The transfected cells were only approximately 5-fold resistant to Taxol. Our results, plus the knowledge that Glu198 is the target for other anti-tubulin agents, suggest that glutamate198 in beta-tubulin is a critical determinant for microtubule stability and Taxol resistance.

Topics: Adenocarcinoma; Alkanes; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Carbamates; Cell Line, Tumor; Cell Survival; Dimerization; Docetaxel; Drug Resistance, Neoplasm; Epothilones; Fluorescent Antibody Technique, Indirect; Glutamic Acid; Glycine; Humans; Lactones; Models, Molecular; Mutation, Missense; Paclitaxel; Protein Structure, Quaternary; Pyrones; Taxoids; Transfection; Tubulin; Tubulin Modulators

Desoxyepothilone B (dEpoB), currently in clinical trials, is a novel microtubule inhibitor with similar mode-of-action to paclitaxel (Taxol). Intriguingly, it is effective in some cell lines and tumor xenografts refractory to Taxol. The purpose of this study is to compare signaling induced by the two drugs and identify a molecular basis for increased efficacy of dEpoB in resistant lines. The importance of ERK signaling, already established for Taxol, was shown for dEpoB and other G2-blocking agents. However, a role in differential sensitivity was not observed. Affymetrix analysis shows similar gene modulation by either agent, alone or in combination with MEK inhibitor. Differential sensitivity in a set of Taxol-resistant lines correlated to the expression of P-glycoprotein (P-gp), and its importance was demonstrated directly. These results suggest that Taxol and dEpoB elicit similar cell death pathways, and the increased efficacy of dEpoB in resistant tumor lines lies in differential susceptibility to P-gp.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Cell Death; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Lung Neoplasms; Paclitaxel; Signal Transduction; Tumor Cells, Cultured

The incidence of recurrent cervical adenocarcinoma is rising relative to the squamous subtype. There are limited therapeutic options for women with advanced cervical adenocarcinoma. Only a few chemotherapy agents have demonstrated activity in this disease. This report describes results with BMS-247550, an epothilone B analog that stabilizes microtubules, with activity in previously treated adenocarcinoma of the cervix.. We present two women with recurrent cervical adenocarcinoma with metastases to the lung. Both women were treated previously with paclitaxel and were enrolled in a phase I study with BMS-247550. Both women had partial responses to BMS-247550 with a decrease in tumor size and CA-125 levels.. The demonstration of a response to BMS-247550, especially after additional chemotherapy had been administered, is encouraging, albeit preliminary. The ultimate role of BMS-247550 and multiagent chemotherapy in the treatment of adenocarcinoma of the cervix should be further investigated.

Topics: Adenocarcinoma; Adult; Antineoplastic Agents; Epothilones; Female; Humans; Lung Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Uterine Cervical Neoplasms

In the current study, we isolated sublines of the human breast adenocarcinoma cell line MDA 435 that exhibited increasing resistance to epothilone A, a microtubule-stabilizing cytotoxic agent. The resistant cells did not express P glycoprotein or multidrug resistance-associated protein (MRP) which are known mediators of multidrug resistance (MDR). Two groups of epothilone A-resistant cells were selected: cells which exhibited low resistance to both epothilone A and Taxol, and cells which exhibit low resistance to Taxol but high resistance to epothilone A. cDNA microarrays of epothilone A-resistant and Taxol-resistant cells were utilized to further characterize epothilone A resistance. Hierarchical clustering of genes according to their levels of expression indicated that the majority of genes which were highly expressed in epothilone A-resistant cells but not in taxol-resistant MDR cells encode known interferon-inducible proteins. Genes whose expression increased with increasing epothilone A resistance include microtubule-associated GTPases, cytoskeletal proteins, cell signalling proteins and a drug metabolising enzyme. The majority of the genes that were repressed in both epothilone A- and Taxol-resistant cells encode proteins regulating cellular growth signalling mechanisms.

Topics: Adenocarcinoma; Antineoplastic Agents; Breast Neoplasms; Cytoskeletal Proteins; Drug Resistance, Neoplasm; Epothilones; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Growth Substances; GTP Phosphohydrolases; HL-60 Cells; Humans; Interferons; Male; Microtubules; Neoplasm Proteins; Paclitaxel; Tumor Cells, Cultured

Peloruside A is a novel secondary metabolite isolated from a New Zealand marine sponge, Mycale hentscheli, that has potent paclitaxel-like microtubule-stabilizing activity and is cytotoxic at nanomolar concentrations. Its 16-membered macrolide ring is similar to that of epothilone, a drug currently under clinical investigation as an anticancer agent. Like paclitaxel, peloruside A arrests cells in the G(2)-M phase of the cell cycle and induces apoptosis. The relatively simple structure of peloruside makes it suitable for the design and synthesis of analogues with improved tumor targeting and reduced tumor cross-resistance.

Topics: Actins; Adenocarcinoma; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle; Epothilones; Humans; Lactones; Lung Neoplasms; Macrolides; Microtubules; Paclitaxel; Taxoids; Tubulin