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.

2009-02-01·Nature Clinical Practice Oncology

Epothilones: tubulin polymerization as a novel target for prostate cancer therapy

Review

作者: W Kevin Kelly ; James J Lee

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.

2008-12-01·Clinical Breast Cancer3区 · 医学

Integrating Epothilones into the Treatment of Patients with Metastatic Breast Cancer: Clinical Perspectives on Incorporating Recent Data in the Practice Setting

3区 · 医学

Review

作者: Linda Vahdat ; Tessa Cigler

The introduction of modern chemotherapy agents, including the taxanes, has improved the prognosis of women with metastatic breast cancer (MBC). Ultimately, however, inevitable intrinsic or acquired resistance to chemotherapy limits treatment options. The epothilones, a novel class of microtubule-stabilizing agents that have incomplete cross-resistance with taxanes and are less susceptible to common mechanisms of resistance, have demonstrated activity in breast cancer. Ixabepilone, the best studied epothilone to date, has been approved for use as a single agent or in combination with capecitabine in anthracycline- and taxanepretreated or refractory MBC. Ixabepilone is relatively well tolerated, with the most common side effects being peripheral neuropathy and neutropenia. Other epothilones such as KOS-862, patupilone, ZK-EPO, BMS-310705, and KOS-1584 are being evaluated as therapy for patients with breast cancer, with promising preliminary data. Ongoing research aims to define and optimize the efficacy of the epothilones in an attempt to improve the quality of life and overall survival of individuals with breast cancer.

100 项与 BMS-310705 相关的药物交易

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