bms-310705 and ixabepilone

Standard cytotoxic chemotherapy of locally advanced or metastatic breast cancer includes the microtubule-stabilizing taxanes, but like other cytotoxic drugs their effectiveness is compromised by resistance that is either inherent or develops during treatment. Epothilones, which also stabilize microtubules but by a different mechanism, are in clinical development primarily to overcome taxane or multidrug resistance, based on potent preclinical antitumor activity against resistant tumor lines. Ixabepilone is the best-studied epothilone clinically and is active in patients with metastatic breast cancer that has been pretreated with, or had established resistance to, taxanes and/or anthracyclines. In a phase III trial in patients with anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer, adding ixabepilone to capecitabine significantly improved progression-free survival and the overall response rate compared with capecitabine alone. The primary toxicities associated with ixabepilone treatment are neuropathy and neutropenia, but both are generally manageable. Other epothilones currently in clinical studies are KOS-862, patupilone, ZK-EPO, BMS-310705, and KOS-1584, which have all shown activity in patients with pretreated or resistant metastatic breast cancer.

Topics: Breast Neoplasms; Capecitabine; Clinical Trials, Phase III as Topic; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Neoplasm Metastasis; Tubulin Modulators

Microtubule-stabilising agents typified by the epothilone class of drug have demonstrated promising activity in Phase II and III clinical trials.. Data supporting the efficacy of these agents are reviewed and their potential use in taxane-refractory disease assessed.. Preclinical evidence assessing the role of the spindle assembly checkpoint in determining the cellular response to microtubule stabilization are presented together with clinical data documenting the efficacy of non-taxane microtubule modulators.. Evidence suggests that microtubule-stabilising agents prolong activation of the spindle assembly checkpoint which may promote cancer cell death in mitosis or following mitotic exit. A weakened spindle assembly checkpoint is associated with altered sensitivity to agents targeting the microtubule and therefore pathways of drug resistance may be shared by these cytotoxic therapies. Preliminary clinical trial data do suggest modest activity of epothilones in truly taxane-resistant patient cohorts, indicating the potential niche for these agents in a molecularly undefined patient group, potentially implicating the role of P-glycoprotein in the acquisition of taxane-resistant disease. Trial data of these antimitotic agents will be presented together with their potential role in taxane-resistant disease and the implications for future clinical trial design.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Transformation, Neoplastic; Chromosomal Instability; Drug Resistance, Neoplasm; Drugs, Investigational; Epothilones; Gene Expression Regulation, Neoplastic; Humans; Microtubules; Mitosis; Neoplasms; Spindle Apparatus; Taxoids; Tubulin Modulators

The epothilones constitute a novel class of microtubule inhibitors that act like the taxanes by hyperstabilizing tubulin polymerization, thus disrupting functioning of the mitotic spindle. Natural epothilones produced by myxobacteria, and second- or third-generation partially or fully synthesized analogs, have been explored as cancer chemotherapy agents to replace or follow the taxanes. For those epothilones that have gone on to clinical development (epothilone B, ixabepilone, BMS-310705, ZK-EPO, KOS-862, and KOS-1584), preclinical investigations in breast cancer models are reviewed. All of these epothilones improve upon the cytotoxic activity of paclitaxel in various human breast cancer cell lines in vitro, but are also highly active in lines that are resistant to paclitaxel. Comparable antitumor activity has been demonstrated against nude mouse xenografts of paclitaxel-sensitive and -resistant breast cancer lines. Additionally, some analogs have reduced toxicity or increased water solubility that may permit oral administration, while others with enhanced tissue penetration show promise in animal models of breast cancer brain or bone metastasis and may provide benefits in patients with poor-prognosis advanced breast cancer.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Capecitabine; Cell Line, Tumor; Clinical Trials, Phase I as Topic; Deoxycytidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Epothilones; Female; Fluorouracil; Humans; Mice; Mice, Nude; Microtubules; Paclitaxel; Tubulin Modulators

For years the microtubule stabilizing agents docetaxel and paclitaxel belong to the most successful clinical chemotherapeutic agents. Several attempts have been made over the years to equal and better these drugs. Both taxanes are associated with the notorious side effect neurotoxicity and are often accompanied with increased drug resistance and cross resistance with other chemotherapeutic agents. In addition their high lipophilicity demands use of co-solvents, which are associated with less favorable side effects such as hypersensitivity. To prevent these disadvantages and improve the clinical application of the taxanes several new agents have entered clinical testing. The agents that are discussed are the drug class of the discodermolides; XAA296A and the epothilones; BMS-247550, BMS-310705, epo906, kos-862 and the agents ABT-751 and D-24851. Here we present an overview of recently performed clinical studies to determine the current state of the art of the tubulin inhibitors which are intended to enlarge and improve the clinical use of the taxanes docetaxel and paclitaxel.

Topics: Epothilones; Humans; Neoplasms; Tubulin Modulators

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

Malignancies are a major cause of morbidity and mortality worldwide. Cancer is a cell disease, characterized by a deviation of the control mechanisms of proliferation and differentiation of cells. Among the treatments available, chemotherapy is often the first choice. Epothilones are a new class of anticancer drugs that act by interacting with cellular microtubules interrupting the proliferation of cancer cells. Many synthetic and semi-synthetic analogues of epothilones have been prepared aiming improvement in effectiveness and tolerability, based on QSAR studies. These analogues have been effective for treatment of tumors resistant to first-line treatments. Six new epothilones are being subjected to clinical trials. Ixabepilone (Ixempra®) was approved by FDA in 2007, patupilone is in phase III clinical trial for ovarian and peritoneum cancer. Sagopilone, desoxiepothilone and KOS-1584 are in phase II clinical trials, for the treatment of recurrent glioblastoma and advanced metastatic breast cancer, metastasic breast cancer and metastatic pulmonary cancer, respectively. Desoxiepothilone reached only phase II trials and BMS-310705 reached phase III/IV trials, but were not approved for clinical use due to adverse effects such as neurotoxicity and severe diarrhea, which were dose-limiting. Furthermore, the low t1/2 (40h) in comparison with other class analogues, does not recommend the clinical use of this derivative. Some other synthetized epothilones presented antineoplastic activity in vitro, but are not yet submitted to clinical studies. Neuropathies and diarrhea are adverse effects presented by some substances of this class of anticancer drugs.

Topics: Animals; Antineoplastic Agents; Bacteria; Benzothiazoles; Epothilones; History, 20th Century; History, 21st Century; Humans; Neoplasms; Structure-Activity Relationship