bms-310705 and Breast-Neoplasms

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

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