Health and Prostate

Overview.

CaP has historically been perceived as chemotherapy-resistant, but the FDA’s recent approval of docetaxel (Aventis’ Taxotere) for hormone-refractory CaP has reversed that perception, and docetaxel is rapidly becoming standard of care for hormone-refractory disease. To achieve success, cytotoxic agents will need to (1) improve upon docetaxel‘s toxicity profile and / or (2) achieve increased survival, either as a monotherapy or in combination with docetaxel. The following sections profile the main candidates. Other cytotoxic agents in development (all Phase II) for which few data are available include amonafide dihydrochloride (ChemGenex Therapeutics’ Quinamed); amonafide malate (Xanthus’ Xanafide, previously XLS-001); and Cell Therapeutic’s BBR-3576, an aza-anthrapyrazole.

Mechanism Of Action.

Cytotoxic agents’ fundamental aim is to exert selective toxicity toward cancer cells. They do so in a variety of ways. The most successful mechanism of action for CaP is microtubule stabilization, which taxanes—most notably docetaxel—cause. Microtubule stabilization prevents the disassembly of these structures, consequently blocking cell division. Epothilones have emerged as a new class of microtubule-targeting drugs. Like taxanes, epothilones induce microtubule bundling, formation of multipolar spindles, and mitotic arrest. Also like taxanes, they induce microtubule polymerization by binding to microtubules and stabilizing microtubule activity. Epothilones are designed to overcome some of the problems associated with taxanes, most notably, susceptibility to resistance caused by the drug efflux protein P-glycoprotein.

Other R&D strategies are focusing on such diverse mechanisms as inducing apoptosis via DNA binding (MGI Pharma’s irofulven [MGI-114]), DNA intercalation (Cell Therapeutics’ BBR-3576), and binding of platinum to DNA (GPC Biotech’s satraplatin [JM-216] and oxaliplatin [DebioPharm's Eloxatin]). The last drug has elicited responses in heavily pretreated patients, but the sparse data preclude further discussion of it.