epothilone-a and Prostatic-Neoplasms

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

Four new therapies have been recently approved for the treatment of men with castration-resistant prostate cancer; still, more treatment options are needed. This review summarizes the data supporting a role for novel chemotherapies including epothilones and immunomodulators (IMiDs), as well as other novel agents within the new landscape of approved therapies.. Epothilones are a class of chemotherapy that target microtubule disassembly, similar to taxanes. Results from phase II studies demonstrating a positive impact on serum prostate-specific antigen for patupilone and sagopilone, current epothilones in development, along with those of ixabepilone, are comparable with historical response rates to docetaxel, the current first-line chemotherapy for castration-resistant disease. IMiDs, including lenalidamide and thalidomide, are also in active development in castration-resistant prostate cancer. A recent phase III study evaluating the combination of lenalidomide and docetaxel revealed decreased overall survival relative to docetaxel alone; however, additional trials are currently recruiting to investigate lenalidomide in various other combination regimens.. Epothilones could be efficacious as an additional therapy in patients who respond to docetaxel chemotherapy. A role for IMiDs, perhaps in combination with chemotherapy or androgen pathway inhibitors, remains to be elucidated.

Topics: Androgen Antagonists; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Design; Drug Resistance, Neoplasm; Epothilones; Humans; Immunologic Factors; Immunotherapy; Male; Microtubules; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Treatment Outcome; Tubulin Modulators; Tumor Microenvironment

Challenges in the discovery of more potent agents to treat the castration-resistant prostate carcinoma (CRPC) reflect the frustrating condition due to development of its drug-resistance in addition to hormone-refractoriness. Although among the different CRPC therapy modalities, the chemotherapy regimens might seem conceptually outclassed as exhibiting a scant tumor cell-selectivity if compared with new molecular mechanism-based agents (so-called "smart drugs"), nevertheless, combo-therapies which combine the chemotherapeutic highly killing potential with specific mechanism-targeting products, seem to be effective antitumor measures. Thus, both microtubule (taxanes, epothilones, noscapine, Vinca-derivatives) and actin filament (pertenotoxins, cytochalasin D)-targeting agents may supply valuable outcomes in CRPC, either alone or in combination with "smart drugs" such as tyrosine- or multi-kinase receptor blockers, mTOR (mammalian target of rapamicin) inhibitors, monoclonal antibodies against various growth factor signaling receptors. Among the microtubule-inhibiting drugs, taxanes are able, by binding the tubulin, to cause polymerization and stabilization of the microtubules with following suppression of their dynamic properties at the mitotic spindle, that results in cancer cell cycle block at G2/M phase together with apoptosis. Cabazitaxel, a novel taxane-based agent, unlike other taxane compounds, exhibits low propensity for P-glycoprotein (Pgp)-mediated plasmalemmal drug efflux pump, thus, avoiding the development of taxane-resistance. Epothylones are a family of novel microtubule-targeting drugs, like taxane inhibiting microtubule dynamic behaviour at mitotic spindle and, therefore, preventing cancer cells from mitosis. Unlike docetaxel and paclitaxel, epothilones maintain their cytotoxic performance even in cancer overexpressing Pgp. Epothilone B-promoted radiosensitivity enhancement has been shown in radioresistant human prostate cancer cells, because such agent is able to delay DNA- strand break repair together with prolonging cell cycle block. To insightfully understand either microtubule or actin filament meshwork-targeting drug pharmacodynamics, functional cytoskeletal features such as cytoskeleton-related molecule cargo logistics, are preliminary taken into consideration.

Topics: Antineoplastic Agents; Carcinoma; Castration; Cytoskeleton; Epothilones; Humans; Male; Prostatic Neoplasms; Taxoids; Tubulin Modulators

Prostate cancer is the most common male cancer and one of the top causes of male cancer-related death in Western countries. Most patients with prostate cancer respond to initial androgen deprivation therapy but eventually progress to castration-resistant prostate cancer (CRPC). Although androgen receptor signaling remains the main driver in CRPC, a growing body of evidence suggests that other pathways are involved in this progression. This article reviews the preclinical data and current status of clinical trials therapeutically targeting tubulin, DNA repair, molecular chaperones such as CLU and Hsp27, tyrosine kinases, and DNA repair.

Topics: Bone Neoplasms; Cell Proliferation; Cell Survival; Dasatinib; Disease Progression; DNA Repair; Epothilones; Gene Fusion; Humans; Male; Neoplasm Invasiveness; Prostatic Neoplasms; Proto-Oncogene Proteins c-met; Pyrimidines; Receptors, Androgen; Taxoids; Thiazoles

The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostate-specific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first- and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC.

Topics: Epothilones; Humans; Male; Prostatic Neoplasms

Topics: Androgen Antagonists; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cancer Vaccines; Epothilones; Estrogens; Genes, bcl-2; Heat-Shock Proteins; Humans; Male; Prostatic Neoplasms; Somatomedins; Treatment Outcome; Tubulin Modulators

Microtubules are vital and dynamic cellular organelles and many agents have been developed that target them. The cytotoxic effects of taxanes and epothilones are mediated by stabilization of microtubule dynamics. Taxanes are one of the most effective cytotoxic agents, and have a broad spectrum of antitumor activity. However, their efficacy is limited by the development of resistance to these effects. Epothilones have a similar mechanism of action to taxanes, but a decreased propensity for drug resistance. Epothilones are macrolides, and have in vitro and in vivo activity in taxane-resistant or taxane-insensitive human cancer cell lines. Several epothilones are in clinical development: ixabepilone, patupilone, BMS-310705, KOS-862, KOS-1584, and ZK-EPO. Multiple dosing schedules of ixabepilone and patupilone have been studied. The toxicity profiles of epothilones are quite diverse and depend on the compound and the administration schedule. The epothilones have demonstrated a wide range of clinical activity, including important antitumor effects, in advanced prostate cancer. Epothilones are particularly useful in patients with prostate cancer who have previously been treated with taxanes or who have taxane-refractory tumors. In the setting of castrate metastatic prostate cancer, ixabepilone and patupilone showed encouraging clinical activity in the phase II setting and further studies are needed to determine if they provide additional clinical benefit to patients with advanced disease.

Topics: Antineoplastic Agents; Cell Line, Tumor; Clinical Trials, Phase II as Topic; Epothilones; Humans; Inhibitory Concentration 50; Male; Molecular Structure; Neoplasm Metastasis; Neutropenia; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Tubulin

Androgen withdrawal or surgical castration remains the standard therapy for advanced prostate cancer disease. Even for castration-resistant prostate cancer the therapeutic option of docetaxel-based chemotherapy is well studied and defined. Facing disease progression after docetaxel-based therapy there are multiple options to continue therapy but the evidence level is rather poor. In the last few years targeted therapy and immunomodulation have been the focus of clinical trials. The presented manuscript intends to provide an overview of classical cytostatic agents, endothelin inhibitors, immunotherapy, modified hormone therapy, multikinase inhibitors and radionuclide approaches which are currently under investigation for implementation in the clinical setting.

Topics: Androgen Antagonists; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Docetaxel; Drug Resistance, Neoplasm; Endothelin Receptor Antagonists; Epothilones; Evidence-Based Medicine; Humans; Immunotherapy; Male; Neoplasm Staging; Orchiectomy; Palliative Care; Practice Guidelines as Topic; Prednisone; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Survival Rate; Taxoids; Tubulin Modulators

There is an urgent need for systemic treatment options for patients with castration-resistant prostate cancer who have progressed after receiving first-line docetaxel chemotherapy. The purpose of this article is to review recent developments in this area.. Retreatment with docetaxel has been employed with evidence of activity in selected populations. Mitoxantrone, the previous first-line standard based on its palliative effect, has also been used with clinical responses observed; however, the symptom benefit in this setting has not been established. Several classes of cytotoxic agents have been tested including platinum agents (satraplatin), epothilones (ixabepilone and patupilone) and taxanes (XRP-6258). A number of targeted therapies have also been clinically evaluated including inhibitors of cytoprotective chaperones (OGX-011) and the vascular endothelial growth factor receptor (sorafenib, sunitinib, and cediranib). An area generating great interest has been the development of agents that target the androgen receptor axis more effectively (MDV3100 and abiraterone) with encouraging early phase trial results.. There is no accepted standard systemic treatment for patients with castration resistant prostate cancer and progressive disease after docetaxel. Novel agents are in phase II and III clinical testing in this setting.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Disease-Free Survival; Docetaxel; Epothilones; Humans; Male; Mitoxantrone; Neoplasm Metastasis; Organoplatinum Compounds; Prostatic Neoplasms; Receptors, Vascular Endothelial Growth Factor; Taxoids; Testosterone; Thionucleotides

Prostate cancer is a significant health concern for men worldwide. It continues to be the most common lethal malignancy diagnosed in American men and the second leading cause of male cancer mortality. Hormone-refractory prostate cancer (HRPC) remains clinically challenging. Two large phase III studies have demonstrated a survival advantage in HRPC patients utilizing docetaxel chemotherapy, setting a new standard of care for this disease. This paper examines the progress that has been made in HRPC with the Taxanes (Docetaxel, Paclitaxel, and Epothilones) with a glimpse on mechanisms of resistance and on combinations able to overcome it. In addition, new targeted therapies under development in combination with taxanes are reviewed with an explanation of their molecular mechanisms of action.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Docetaxel; Drug Administration Schedule; Epothilones; Humans; Male; Neoplasms, Hormone-Dependent; Paclitaxel; Prostatic Neoplasms; Taxoids

Hormone-refractory prostate cancer (HRPC) is a progressive chemotherapy-resistant disease that remains a challenge to manage. Despite the recent approval of docetaxel (Taxotere) for the treatment of HRPC, the need exists for additional novel agents that can further improve patient outcomes. The epothilones are potent antimicrotubule agents that have demonstrated activity in the setting of taxane resistance. They are structurally distinct compounds that appear to lack cross-resistance with the taxanes.. This review summarizes current preclinical and clinical data on the safety and efficacy of the epothilones ixabepilone (BMS-247550) and patupilone (EPO906) for the treatment of prostate cancer. Data were identified by searches of PubMed and the Proceedings of the American Society of Clinical Oncology annual meetings from 2000 to 2006.. The epothilones have demonstrated potent antitumor activity in vitro and in experimental animal models of prostate cancer. In clinical studies, the epothilones have demonstrated potent activity in HRPC, including no cross-resistance with the taxanes and a manageable toxicity profile. Phase II studies of single-agent ixabepilone in patients with HRPC have reported a confirmed prostate-specific antigen (PSA) response rate of 33%. Higher PSA response rates have been reported in studies that assessed the combination of ixabepilone and estramustine in patients with HRPC.. The epothilones are promising new chemotherapeutic agents that have demonstrated single-agent antitumor activity in HRPC in the phase II setting. Phase III trials are needed to confirm the activity of the epothilones in tandem with docetaxel, given the experience to date.

Topics: Animals; Antineoplastic Agents; Docetaxel; Epothilones; Humans; In Vitro Techniques; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Tubulin Modulators

Although the number of men presenting with metastatic prostate cancer has decreased significantly over the last several years, the death rate for those men is essentially unchanged. Effective treatments have not existed for prostate cancer progressing after androgen deprivation therapy until recently. Docetaxel based chemotherapy has demonstrated to extend patient survival in two large randomized studies. These studies have provided the impetus to combine docetaxel with novel biologic drugs to further consolidate the gains in long-term outcome. With the arrival of new therapies such as epothilone analogues, small molecule receptor tyrosine kinase inhibitors, monoclonal antibodies, bone-targeted drugs, antisense oligonucleotides, antiangiogenics drugs and endothelin receptor antagonists, the future of prostate cancer therapy appears promising.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents; Boronic Acids; Bortezomib; Calcitriol; Cancer Vaccines; Diphosphonates; Docetaxel; Drug Resistance, Neoplasm; Endothelin-1; Epothilones; Humans; Male; Oligonucleotides, Antisense; Organoplatinum Compounds; Prostatic Neoplasms; Protease Inhibitors; Protein Kinase Inhibitors; Pyrazines; Taxoids

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

Epothilones are cytotoxic macrolides with a similar mechanism of action to paclitaxel but with the potential advantage of activity in taxane-resistant settings in preclinical models. The epothilones ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO are in early clinical trials for cancer treatment. Phase I studies have shown that dose-limiting toxicities of epothilones are generally neurotoxicity and neutropoenia although initial studies with patupilone indicated that diarrhoea was dose limiting. Neuropathy induced by ixabepilone may be schedule dependent. Over 20 Phase II studies of epothilones in cancer treatment have been reported, and significant activity in taxane-sensitive tumour types (such as breast, lung and prostate cancers) has been noted. Response rates in taxane-refractory metastatic breast cancer are relatively modest, but ixabepilone and patupilone have shown promising efficacy in hormone-refractory metastatic prostate cancer and in taxane-refractory ovarian cancer.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Lung Neoplasms; Male; Prostatic Neoplasms; Tubulin Modulators

2004 was a critical year for advances in prostate cancer treatment. The results from two pivotal multicenter phase III randomized studies are the first to demonstrate a survival benefit associated with chemotherapeutic treatment interventions in patients with hormone-refractory prostate cancer. This review will focus on an interpretation of the data from these two studies, the emerging role for chemotherapy in 2005 and beyond, and ongoing areas of clinical research.. Phase I and II studies have demonstrated biochemical and objective responses achieved with docetaxel-based chemotherapy in men with hormone-refractory prostate cancer. Two pivotal phase III clinical trials, TAX 327 and SWOG 9916 have demonstrated a survival advantage of docetaxel-based chemotherapy over mitoxantrone. Novel targeted therapies under investigation include calcitriol, growth factor-targeted agents, epothilones and others.. We now have a new standard of care for men with metastatic hormone-refractory prostate cancer. Further investigation of docetaxel-based regimens in earlier clinical states of disease is warranted and may demonstrate greater clinical benefit. Additional chemotherapy agents are being studied, and may also add to the future armamentarium available for prostate cancer. The enrolment of patients into these studies is critical to the ongoing evolution of prostate cancer management.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Calcitriol; Calcium Channel Agonists; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epothilones; Estramustine; Humans; Male; Mitoxantrone; Multicenter Studies as Topic; Prednisone; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Epothilones; Estramustine; Humans; Male; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

Topics: Adult; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Clinical Trials, Phase II as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Epothilones; Humans; Male; Middle Aged; Neoplasm Staging; Prognosis; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk Assessment; Survival Analysis; Treatment Outcome

Prostate cancer is a leading cause of morbidity and mortality among males. Androgen ablation as initial therapy for advanced prostate cancer provides high response rates but does not cure disease, as nearly all men with metastases will eventually progress to hormone-refractory prostate cancer (HRPC). Present chemotherapy regimens for HRPC can provide palliation and have recently demonstrated an increase in overall survival. Over the past 2 decades, these regimens represent clear advances in the treatment of metastatic prostate cancer but also demonstrate that newer therapies are needed. Studies are ongoing to provide viable alternatives among traditional cytotoxic therapies as well as among novel agents targeting specific molecular pathways. This article reviews some of the newer therapies being developed and evaluated, including the epothilone analogues, human epidermal growth factor receptor pathway inhibitors, angiogenesis inhibitors, and endothelin receptor antagonists.

Topics: Angiogenesis Inhibitors; Clinical Trials as Topic; Endothelin Receptor Antagonists; Epothilones; ErbB Receptors; Humans; Male; Neoplasm Metastasis; Palliative Care; Prostatic Neoplasms; Receptor, ErbB-2

Hormone refractory prostate cancer (HRPC) remains a challenge in the management of prostate cancer patients. With the widespread use of PSA (prostate specific antigen), recurrent disease after local treatment for localised prostate cancer is usually diagnosed long before evidence of metastatic disease. In many cases, hormonal manipulations are started at the time of biochemical relapse and therefore, patients become 'hormone refractory' earlier in the course of their disease, frequently with a good performance status, often with no evidence of metastatic disease, and they still face a considerably long life expectancy. Despite these changes, the need for more options in the treatment of HRPC is obvious. The pharmacological treatments that are in use and those that are under investigation for this group of patients will be discussed and include: cytotoxic agents including the microtubule inhibitors, alone and in combination with other conventional or experimental therapies such as calcitriol or thalidomide; treatment with epothilone analogues; endothelin receptor antagonists; palliative therapy with bisphosphonates, bone-targeted radiopharmaceuticals and other developing treatments such as vaccines, gene therapies and monoclonal antibodies.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Calcitriol; Clinical Trials as Topic; Diphosphonates; Endothelin Receptor Antagonists; Epothilones; Humans; Male; Metalloendopeptidases; Prostatic Neoplasms; Thalidomide; Vitamin D

The purpose of this study was to determine the clinical activity of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel.. Eligible patients had progressive disease within 6 months of receiving docetaxel. Patupilone was administered 10 mg/m2 i.v. every 3 weeks. The primary end point was the proportion of patients with a confirmed≥50% prostate-specific antigen (PSA) decline.. Eighty-three patients were enrolled. At baseline, the median time to progression after prior docetaxel was 1.4 months (range 0-5.7). Gastrointestinal serious adverse events occurred in four of the six initial patients leading to a reduction of the starting dose of patupilone to 8 mg/m2 for subsequent patients. Grade 3-4 toxicity at this dose included diarrhea (22%), fatigue (21%), and anorexia (10%). One patient experienced grade 3-4 hematologic toxicity. A PSA decline of ≥50% occurred in 47% of patients. A partial measurable disease response occurred in 24% of assessable patients. A patient-reported pain response was observed in 59% of assessable patients. Median time to PSA progression was 6.1 months [95% confidence interval (CI) 4.7-8.0] and median overall survival was 11.3 months (95% CI 9.8-15.4).. Patupilone at 8 mg/m2 was tolerable, had antitumor activity, and was associated with symptomatic improvement in patients previously treated with docetaxel.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Canada; Castration; Disease-Free Survival; Docetaxel; Epothilones; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Salvage Therapy; Taxoids

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

Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to investigate the activity and safety of sagopilone in patients with metastatic castration-resistant PC (CRPC).. Chemotherapy-naïve patients with metastatic CRPC received sagopilone (one cycle: 16 mg m(-2) intravenously over 3 h q3w) plus prednisone (5 mg twice daily). The primary efficacy evaluation was prostate-specific antigen (PSA) response rate (≥50% PSA reduction confirmed ≥28 days apart). According to the Simon two-stage design, ≥3 PSA responders were necessary within the first 13 evaluable patients for recruitment to continue until 46 evaluable patients were available.. In all, 53 patients received ≥2 study medication cycles, with high compliance. Mean individual dose was 15.1±1.4 mg m(-2) during initial six cycles, mean dose intensity 94±9%. The confirmed PSA response rate was 37%. Median overall progression-free survival was 6.4 months. The most commonly reported adverse events (>10% of patients) were peripheral neuropathy (94.3%), fatigue (54.7%) and pain in the extremities (47.2%). Sagopilone was associated with very little haematological toxicity.. This study shows that first-line sagopilone has noteworthy anti-tumour activity and a clinically significant level of neuropathy for patients with metastatic chemotherapy-naïve CRPC.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Epothilones; Humans; Male; Middle Aged; Orchiectomy; Prednisone; Prognosis; Prospective Studies; Prostatic Neoplasms

Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second-line chemotherapy in patients with docetaxel-refractory castration-resistant prostate cancer. Clinical noncross- resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose-limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination.. Patients with metastatic progressive castration-resistant prostate cancer during or after 3 or more cycles of taxane-based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m(2) and mitoxantrone 12 mg/m(2) administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity.. Results are reported for the 56 evaluable patients. Twenty-five (45%; 95% confidence interval [CI], 31%-59%) experienced confirmed ≥ 50% prostate-specific antigen (PSA) declines, 33 (59%; 95% CI, 45%-72%) experienced confirmed ≥ 30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%-39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and median progression-free survival was also 4.4 months (95% CI, 3.0-6.0). Median overall survival was 12.5 months (95% CI, 10.2-15.9). Thirty-two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment-related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively.. These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration-resistant prostate cancer and requires dosing with pegfilgrastim.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Epothilones; Humans; Male; Middle Aged; Mitoxantrone; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Orchiectomy; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Treatment Outcome

Drug resistance mechanisms can reduce response rate and duration in men with castration-resistant prostate cancer (CRPC) receiving docetaxel-based therapy. Patupilone (epothilone B), a microtubule-targeting agent, may be unaffected by some resistance mechanisms. Therefore, a phase II study assessed the patupilone safety and activity in CRPC patients with and without previous chemotherapy.. CRPC patients received patupilone 2.5 mg/m(2) weekly for 3 weeks of a 4-week cycle. Patients were required to have measurable disease or prostate-specific antigen (PSA) progression (levels>20 ng/ml).. All 45 enrolled patients (median age, 69 years) were safety and response assessable. Sixty-four percent had previous chemotherapy (55% had previous taxane therapy). Patients received a median of three patupilone cycles. Patupilone was generally well tolerated. Ten (22%) patients experienced grade 3 diarrhea, six (13%) grade 3 fatigue, and one (2%) grade 3 neuropathy with no neutropenia or thrombocytopenia incidence. Six (13%) patients had >or= 50% decline in PSA (three had previous taxane therapy). No patient with measurable disease had a response. Median overall survival was 13.4 months.. The safety profile of weekly patupilone in CRPC patients compares favorably with that of other microtubule inhibitors. At the dose and schedule tested, patupilone demonstrated minimal activity in CRPC.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Epothilones; Humans; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms

To determine if ixabepilone is a substrate for cytochrome P450 3A4 (CYP3A4) and if its metabolism by this cytochrome is clinically important, we did a clinical drug interaction study in humans using ketoconazole as an inhibitor of CYP3A4.. Human microsomes were used to determine the cytochrome P450 enzyme(s) involved in the metabolism of ixabepilone. Computational docking (CYP3A4) studies were done for epothilone B and ixabepilone. A follow-up clinical study was done in patients with cancer to determine if 400 mg/d ketoconazole (inhibitor of CYP3A4) altered the pharmacokinetics, drug-target interactions, and pharmacodynamics of ixabepilone.. Molecular modeling and human microsomal studies predicted ixabepilone to be a good substrate for CYP3A4. In patients, ketoconazole coadministration resulted in a maximum ixabepilone dose administration to 25 mg/m(2) when compared with single-agent therapy of 40 mg/m(2). Coadministration of ketoconazole with ixabepilone resulted in a 79% increase in AUC(0-infinity). The relationship of microtubule bundle formation in peripheral blood mononuclear cells to plasma ixabepilone concentration was well described by the Hill equation. Microtubule bundle formation in peripheral blood mononuclear cells correlated with neutropenia.. Ixabepilone is a good CYP3A4 substrate in vitro; however, in humans, it is likely to be cleared by multiple mechanisms. Furthermore, our results provide evidence that there is a direct relationship between ixabepilone pharmacokinetics, neutrophil counts, and microtubule bundle formation in PBMCs. Strong inhibitors of CYP3A4 should be used cautiously in the context of ixabepilone dosing.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Computational Biology; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Epothilones; Female; Genital Neoplasms, Female; Humans; Ketoconazole; Leukocytes, Mononuclear; Liver; Liver Neoplasms; Male; Microsomes, Liver; Middle Aged; Neoplasms; Prostatic Neoplasms; Tubulin Modulators

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

Based on the pre-clinical spectrum of activity in taxane-resistant cell lines, we evaluated KOS-862 (epothilone D; 12,13-desoxyepothilone B) as second-line chemotherapy in androgen-independent prostate cancer.Thirty-eight men with metastatic androgen-independent prostate cancer and evidence of progression following docetaxel-based chemotherapy were treated with KOS-862, 100 mg/m(2) (maximum of 240 mg) i.v. weekly for 3 weeks, repeated every 4 weeks. The primary objective for this study was to determine the antitumor activity, measured by PSA decline by more then 50% confirmed 4 weeks later. Two patients (5.3%, 90% CI 1-16%) met criteria for confirmed PSA decline. While both of these patients had previously been treated with docetaxel, neither had confirmed docetaxel-refractory disease. None of the 24 patients with measurable disease had a confirmed partial response. Seventy-three percent of patients had an adverse event leading to dose delay, reduction, or treatment discontinuation. Neurological toxicity and fatigue predominated. Seventeen patients (44.7%) had treatment related grade 3 neurological adverse events including peripheral sensory neuropathy (n = 4, 10.5%), ataxia (n = 3, 7.9%), peripheral motor neuropathy (n = 1, 2.6%), involuntary muscle contractions (n = 1, 2.6%) and neuropathic pain (n = 1, 2.6%). One subject (2.6%) had a grade 4 treatment peripheral motor neuropathy. Further study of this dose and schedule of KOS-862 in this patient population cannot be recommended due to both lack of activity and excessive toxicity.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Epothilones; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Taxoids; Treatment Outcome

To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer.. Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5.. Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm.. Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Castration; Epothilones; Estramustine; Fatigue; Humans; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Peripheral Nervous System Diseases; Prostatic Neoplasms; Thrombosis

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

Taxanes are widely employed chemotherapies for patients with metastatic prostate and breast cancer. Here, we show that loss of Diaphanous-related formin-3 (DIAPH3), frequently associated with metastatic breast and prostate cancers, correlates with increased sensitivity to taxanes. DIAPH3 interacted with microtubules (MT), and its loss altered several parameters of MT dynamics as well as decreased polarized force generation, contractility, and response to substrate stiffness. Silencing of DIAPH3 increased the cytotoxic response to taxanes in prostate and breast cancer cell lines. Analysis of drug activity for tubulin-targeted agents in the NCI-60 cell line panel revealed a uniform positive correlation between reduced DIAPH3 expression and drug sensitivity. Low DIAPH3 expression correlated with improved relapse-free survival in breast cancer patients treated with chemotherapeutic regimens containing taxanes. Our results suggest that inhibition of MT stability arising from DIAPH3 downregulation enhances susceptibility to MT poisons, and that the DIAPH3 network potentially reports taxane sensitivity in human tumors.

Topics: Adaptor Proteins, Signal Transducing; Breast Neoplasms; Epothilones; Female; Formins; Gene Silencing; Humans; Male; Microtubules; Prostatic Neoplasms; Taxoids

Castrate-resistant prostate cancer (CRPC) is a challenging aspect in the treatment of prostate cancer. Research has identified several pathways in the pathogenesis of CRPC. Several new agents targeting some of these pathways have shown promising data during clinical trials. In the area of androgen depletion, abiraterone acetate and MDV100 have been studied and have shown to decrease prostate-specific antigen (PSA) levels in phase I and II studies. Bevacizumab is a monoclonal antibody antiangiogenesis agent that targets vascular endothelial growth factor (VEGF) and has shown to decrease PSA levels in combination with other cytotoxic agents. Three agents, ixabepilone, patupilone, and sagopilone, in the class of epothilones (tubulin polymerizing antitumor agents), have shown moderate reductions in PSA levels and moderate adverse effects. The results of ongoing studies with these new treatment agents may offer viable alternatives to the traditional treatment of CRPC to decrease disease progression and improve overall survival.

Topics: Androstenes; Androstenols; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Bevacizumab; Clinical Trials as Topic; Epothilones; Humans; Male; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase; Tubulin Modulators

Despite that greater knowledge of prostate cancer biology has led to the isolation of many new and promising targets, treatment of metastatic prostate cancer is still challenging. New agents targeting these molecules are currently under development in large randomized phase III trials, to improve overall survival and the quality of life of patients with metastatic castrate-resistant prostatic cancer (CRPC). Cytotoxic chemotherapy (docetaxel-based chemotherapy) demonstrated clinical benefit on overall survival, but could be improved. Drugs targeting directly or not the androgen receptor such as abiraterone or new specific peripheral anti-androgens (MDV3100) are very promising. Bone targeted therapies (endothelin1 receptor A inhibitor, RANK ligant, metabolic irradiation) are also very promising and are in development in large phase III trials. Antiangiogenic therapies could also be effective in CRPC. Autologous vaccin against prostatic acid phosphatase seems to prolong overall survival and other vaccin and immunotherapy strategies are in development (anti-CTLA4 antibody). A recent analogue of thalidomide, probably more efficient, lenalidomide is also in development.

Topics: Androgen Antagonists; Androstenes; Androstenols; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Bone Neoplasms; Castration; Denosumab; Epothilones; ErbB Receptors; Furans; Humans; Immunotherapy; Ketones; Male; Orchiectomy; Prostatic Neoplasms; Pyrrolidines; RANK Ligand

In metastatic prostate cancer, DOC-2/DAB2 interactive protein (DAB2IP) is often downregulated and has been reported as a possible prognostic marker to predict the risk of aggressive prostate cancer (PCa). Our preliminary results show that DAB2IP-deficient PCa cells are radioresistant. In this study, we investigated the anticancer drug Epothilone B (EpoB) for the modulation of radiosensitivity in DAB2IP-deficient human PCa cells.. We used a stable DAB2IP-knock down human PCa cell line, PC3 shDAB2IP, treated with EpoB, ionizing radiation (IR), or the combined treatment of EpoB and IR. The modulation of radiosensitivity was determined by surviving fraction, cell cycle distribution, apoptosis, and DNA double-strand break (DSB) repair. For in vivo studies, the PC3shDAB2IP xenograft model was used in athymic nude mice.. Treatment with EpoB at IC(50) dose (33.3 nM) increased cellular radiosensitivity in the DAB2IP-deficient cell line with a dose enhancement ratio of 2.36. EpoB delayed the DSB repair kinetics after IR and augmented the induction of apoptosis in irradiated cells after G(2)/M arrest. Combined treatment of EpoB and radiation enhanced tumor growth delay with an enhancement factor of 1.2.. We have demonstrated a significant radiation dose enhancement using EpoB in DAB2IP-deficient prostate cancer cells. This radiosensitization can be attributed to delayed DSB repair, prolonged G(2) block, and increased apoptosis in cells entering the cell cycle after G(2)/M arrest.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Combined Modality Therapy; DNA Breaks, Double-Stranded; DNA Repair; Epothilones; G2 Phase; Gene Knockdown Techniques; Humans; Male; Mice; Mice, Nude; Mitosis; Neoplasm Proteins; Prostatic Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents; ras GTPase-Activating Proteins; Xenograft Model Antitumor Assays

Mitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapy in docetaxel-refractory castration-resistant prostate cancer (CRPC) patients. Clinical noncrossresistance was previously observed.. Metastatic CRPC patients progressing during or after taxane-based chemotherapy enrolled in a phase I multicenter study of ixabepilone and mitoxantrone administered every 21 days along with prednisone. Ixabepilone and mitoxantrone doses were alternately escalated in a standard 3 + 3 design. Patients were evaluated for toxicity and disease response. Dose-limiting toxicities (DLTs) were defined as treatment related, occurring during cycle 1, and included grade 4 prolonged or febrile neutropenia, thrombocytopenia (grade 4 or grade 3 with bleeding), or > or = grade 3 nonhematologic toxicity.. Thirty-six patients were treated; 59% of patients experienced grade 3/4 neutropenia. DLTs included grade 3 diarrhea (n = 1), prolonged grade 4 neutropenia (n = 4), and grade 5 neutropenic infection (n = 1). Due to prolonged neutropenia, the highest dose levels were repeated with pegfilgrastim on day 2 of each cycle. The maximum tolerated dose in combination with pegfilgrastim was not exceeded. The recommended phase II dose is mitoxantrone 12 mg/m2 and ixabepilone 35 mg/m2 every 21 days, pegfilgrastim 6 mg subcutaneously day 2, and continuous prednisone 5 mg twice per day. Thirty-one percent of patients have experienced > or = 50% prostate-specific antigen (PSA) declines, and two experienced objective responses. Of 21 patients treated with mitoxantrone 12 mg/m2 plus ixabepilone > or = 30 mg/m2, nine (43%) experienced > or = 50% PSA declines (95% CI, 22% to 66%).. These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Castration; Docetaxel; Epothilones; Humans; Infusions, Subcutaneous; Male; Middle Aged; Military Personnel; Mitoxantrone; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids

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

Epothilones and taxanes interfere with microtubule function. Ixabepilone, which is an epothilone-B analog, has activity against taxane-resistant cell lines and as first-line therapy for men with hormone-refractory prostate carcinoma (HRPC). Clinical cross-resistance of ixabepilone and taxanes in HRPC is unknown.. Records were evaluated retrospectively from patients with HRPC who were treated on a randomized Phase II trial of ixabepilone with or without estramustine and who subsequently received taxane chemotherapy. Posttherapy declines in prostate-specific antigen (PSA) levels and time to PSA progression were defined by consensus criteria. The median survival was evaluated by using the Kaplan-Meier method.. Forty-nine patients who received ixabepilone with estramustine (28 patients) or without estramustine (21 patients) subsequently received second-line taxane therapy. Second-line PSA declines > or = 50% were achieved by 51% of patients (95% confidence interval [95% CI], 33-66%). Second-line PSA declines > or = 50% were achieved by 61% of patients (95% CI, 42-78%) who achieved a first-line PSA decline > or = 50% with ixabepilone, compared with 33% of patients (95% CI, 13-59%) who did not (P = 0.08). Patients who discontinued first-line ixabepilone treatment for disease progression were less likely to achieve a PSA decline > or = 50% in response to second-line, taxane-based therapy compared with patients who discontinued for toxicity or patient preference (36% vs. 71%; P = 0.01).. Second-line taxane chemotherapy after ixabepilone resulted in a substantial frequency of PSA declines. Although patients with ixabepilone-refractory disease were less likely to respond to second-line taxane chemotherapy, 36% did achieve a PSA response. These findings were consistent with incomplete clinical cross-resistance between the taxanes and the epothilones.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Epothilones; Estramustine; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Taxoids; Treatment Outcome

Microtubule agents appear promising for the treatment of prostate cancer. Patupilone (epothilone B), a highly potent non-taxane microtubule stabilizing agent, was evaluated in models of androgen-independent prostate cancer.. Patupilone was administered to athymic mice bearing human prostate cancer xenografts (subcutaneous DU 145 and PC-3M, orthotopic PC-3M).. One 4 mg/kg patupilone administration produced transient regression of DU 145 tumors, while two weekly administrations of 2.5 mg/kg produced stable disease followed by protracted regression, however with more pronounced body weight loss. Taxol (15 mg/kg every other day) weakly inhibited tumor growth, but with less body weight loss. Patupilone (5 mg/kg) produced protracted growth inhibition of subcutaneous PC-3M tumors, with transient body weight loss. In mice with orthotopic PC-3M tumors, 4 or 5 mg/kg/week patupilone impaired primary tumor growth, abrogated metastases and enhanced survival, with only transient body weight loss.. These data suggest that patupilone holds promise for prostate cancer treatment.

Topics: Animals; Antineoplastic Agents; Body Weight; Cell Line, Tumor; Epothilones; Humans; Lymphatic Metastasis; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Paclitaxel; Prostatic Neoplasms; Xenograft Model Antitumor Assays

Epothilones are a promising class of drugs in clinical trials of prostate cancer that target the microtubules, similar to taxanes, and induce apoptosis in taxane resistant tumors. The tumor suppressor p53 is one important molecular mechanism of chemotherapy resistance that in some studies predicted tumor sensitivity to paclitaxel. We hypothesized that epothilone induced cytotoxicity would be influenced by the status of p53 in prostate cells.. LNCaP, DU145, and a transformed rat prostate (RP) epithelial cell line with a temperature sensitive mutant p53 (val 135) were studied for the effect of epothilone on cell viability, cell cycle, and cell cycle checkpoint proteins.. Epothilone had greater cytotoxicity in p53 mutant cancer cells compared to wild type cells. We confirmed our findings by creating a transformed RP epithelial cell line with a temperature sensitive mutant p53 (val 135). Using a tetrazolium (MTT) assay we found that epothilone (100 nM) decreased cell viability in RP cells by 90% with mutant p53 compared to 45% with wild type p53 (P < 0.01). Epothilone induced G2/M arrest in 50% of cells with mutant p53 compared to 25% with wild type p53 (P < 0.01). To begin to understand mechanism of epothilone induced G2/M arrest, we assessed cell cycle checkpoint proteins. We found that the effect to enhance G2/M cell cycle arrest was associated with dephosphorylation of cdc2 in both p53 wild type and p53 mutant RP cells.. These results demonstrate that epothilone is more active against transformed prostate epithelial cells with mutant compared to wild type p53. Epothilone is capable of dephosphorylation of cdc2 in both p53 wild type and mutant cells, which is associated with G2/M cell cycle arrest. These data provide a basis for further study of p53, and the phosphorylation status of cdc-2, as markers for epothilone sensitivity in clinical studies.

Topics: Animals; Antineoplastic Agents; Cell Line, Transformed; Cell Survival; Epithelial Cells; Epothilones; G2 Phase; Male; Mitosis; Prostatic Neoplasms; Rats; Tumor Suppressor Protein p53

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Docetaxel; Epothilones; Goserelin; Humans; Male; Medical Oncology; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

Epothilone compounds (e.g. epothilones A and B) represent a new structural class of microtubule inhibitors with the remarkable ability to inhibit tumor growth of multidrug-resistant cell lines at low nanomolar or even subnanomolar concentrations. Unfortunately, this therapeutic efficacy has only been achieved to date with a narrow therapeutic window. Hence, other structural analogs of compounds such as epothilone B are currently being synthesized in the hope that they will demonstrate equivalent antitumor efficacy with reduced systemic toxicity.. To evaluate the relative efficacy and toxicity of selectively modified epothilone compounds.. Compounds were initially screened for relative cytotoxicity against the human prostate cancer cell lines PC3, LNCaP, MDA PCa 2a and MDA PCa 2b. Growth inhibitory IC50 values of 0.5 to 4 nM were obtained. From this initial screen, one epothilone compound, 26-fluoroepothilone B, was chosen for further evaluation against the growth of s.c.-implanted MDA PCa 2b- and PC3-derived prostate tumors in athymic nude mice. The compound was administered intravenously at 2, 5 and 10 mg/kg after the tumors had reached 300 mm3. Two control groups were used: paclitaxel (40 mg/kg) and saline.. Following treatment with 10 mg 26-fluoroepothilone B/kg, there was a sustained decrease in tumor size for 30 days reaching a maximal reduction of 80% when compared with tumor growth in the saline control group. Sustained suppression (> 20 days) of tumor growth was observed following the second drug injection. Although a maximal body weight loss of 30% occurred after the second injection, all mice completely regained their initial body weight in 20 days. A lower dose (2 mg/kg) produced a 58% maximal reduction in tumor size and a 20% body weight loss. Minimal inhibition of tumor growth, however, was obtained with paclitaxel at a maximally tolerated dose (40 mg/kg). Other epothilones tested were either less effective and/or more toxic than 26-fluoroepothilone B. This new fluorinated epothilone compound supports the growth of paclitaxel-dependent Tax-18 mutant CHO cells and produces microtubule bundles similar to those produced by paclitaxel, indicating that the two drugs share a similar mechanism of action.. A new fluorinated epothilone compound, 26-fluoroepothilone B, has been described that stabilizes microtubule structures based on its support of growth of a mutant paclitaxel-dependent CHO cell line. Its antitumor activity against human prostate cancer in nude mice is superior to that of paclitaxel at equivalent toxic doses. Further research is required to determine optimal dosing strategies and to fully assess the compound's activity against other malignant diseases.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Epothilones; Humans; Infusions, Intravenous; Macrolides; Male; Mice; Mice, Nude; Paclitaxel; Prostatic Neoplasms; Transplantation, Heterologous; Tumor Cells, Cultured