Molecular determinants of apoptosis induced by cytotoxic drugs.

Recent experimental evidence suggests that apoptosis pathways such as the CD95 system are an important mediator of chemotherapy-induced apoptosis in various tumor cell lines. Therapeutic concentrations of cytotoxic drugs induce CD95 and CD95-L that mediates apoptosis via an autocrine/paracrine loop by crosslinking CD95. Interfering with CD95-L/receptor interaction by antagonistic antibodies to the receptor or by inhibition of CD95-L expression strongly reduces apoptosis. Drug-induced apoptosis critically depends on activation of caspases since apoptosis is almost completely abrogated by the caspase inhibitor zVAD-fmk. The receptor apical caspase FLICE/MACH (caspase-8) and the downstream caspase CPP32 (caspase-3) are cleaved resulting in processing of substrates such as the nuclear enzyme PARP. In addition, the response to cytotoxic drugs is modulated by pro- and antiapoptotic proteins of the Bcl-2 family and p53. Defects in apoptosis pathways, e.g. deficient upregulation of CD95-L, downregulation of CD95 expression or blockade of caspase activation may confer resistance to cytotoxic drug treatment. Thus, chemosensitivity of tumor cells depends on intact apoptosis pathways such as the CD95 system that are activated by chemotherapeutic drugs. These findings may have implications for drug sensitivity and resistance of tumor cells.