Mechanisms of action of taxanes in prostate cancer.
Taxanes appear to have significant clinical activity in hormone-refractory prostate cancer and are entering increasing numbers of clinical trials. In general, they appear to initiate the apoptotic process by binding to beta-tubulin and promoting its polymerization. However, it is possible, at least in prostate cancer cell lines, that the ultimate decision for or against apoptosis may be modulated by a number of factors, including levels of Bcl-family members, especially the antiapoptotic proteins bcl-2 and bcl-xL. Differences in the cellular pharmacology of docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) and paclitaxel have been identified. Docetaxel has a somewhat higher affinity for microtubules than paclitaxel (approximately twofold), and in some circumstances may be a more potent inducer of bcl-2 phosphorylation. However, it is not clear whether these docetaxel-induced events are directly related to its antiprostate cancer effects. In murine macrophages, paclitaxel, but not docetaxel, induces several proinflammatory genes, but it is not known whether this occurs in prostate cancer cells. The mechanisms of cytotoxicity of taxanes in prostate cancer are undoubtedly complex and will require considerable additional study to fully understand.
Stein
C A
CA
Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D000077143:Docetaxel; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D008870:Microtubules / Q000187:drug effects; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects; D043823:Taxoids; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects
D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D000077143:Docetaxel; D017239:Paclitaxel