Promises and challenges of targeting Bcl-2 anti-apoptotic proteins for cancer therapy.

Cancer cells with elevated levels of BCL-2 and related survival proteins are broadly resistant to cytotoxic agents. Antisense oligodeoxynucleotides, and more recently small molecule ligands for BCL-2 and BCL-XL, are directly cytotoxic or synergistic with standard cytotoxic agents, and in some cases, may demonstrate selectivity for tumor cells. The usual issues for rational drug discovery are writ large upon BCL-2-targeted therapeutics. The molecular functions of BCL-2 are not well understood, such that validation of cytotoxic mechanisms related to BCL-2 as well as identification of surrogate markers for BCL-2 function are significant obstacles for drug development. Despite these problems, a substantial number of small molecules that bind to BCL-2 or BCL-XL are now available for pre-clinical testing; in turn, basic studies with these reagents should yield new insights about optimal strategies to disrupt BCL-2 survival functions.