PLATINUM RESISTANCE - LABORATORY FINDINGS AND CLINICAL IMPLICATIONS

Platinum compounds are universally recognized as one of the most impor tant classes of chemotherapeutic agents for the treatment of cancer. E mergence of resistance to cisplatin has appeared, however, to be a maj or prognostic factor of adverse outcome in the otherwise most sensitiv e of malignancies: testicular and ovarian cancers. After a decade of t esting both systemic and regional dose-intensification of cisplatin an d its analog carboplatin-which is more amenable to dose escalation wit h cytokines and bone marrow progenitor cell support-a plateau is appar ent even in sensitive tumor types beyond which additional dose escalat ions do not appreciably increase response. Laboratory work searching f or causes of intrinsic and acquired resistance, providing early indica tion of drug sensitivity, and developing strategies for restoring or o vercoming resistance is ongoing and is guiding clinical studies and dr ug development. Causes of cellular resistance to platinums are complex and include decreased drug accumulation, increased detoxification, in creased repair of DNA-platinum adducts, and increased tolerance of DNA lesions. Clinical trials are already ongoing regarding strategies inv olving protection of specific toxicities, decreasing intracellular glu tathione (by buthionine sulfoximine), decreasing DNA repair, and intro ducing new analogs that are able to overcome certain forms of platinum resistance.