Platinum resistance: laboratory findings and clinical implications

Abstract

Platinum compounds are universally recognized as one of the most important classes of chemotherapeutic agents for the treatment of cancer. Emergence of resistance to cisplatin has appeared, however, to be a major prognostic factor of adverse outcome in the otherwise most sensitive of malignancies: testicular and ovarian cancers. After a decade of testing both systemic and regional dose-intensification of cisplatin and its analog carboplatin--which is more amenable to dose escalation with cytokines and bone marrow progenitor cell support--a plateau is apparent even in sensitive tumor types beyond which additional dose escalations do not appreciably increase response. Laboratory work searching for causes of intrinsic and acquired resistance, providing early indication of drug sensitivity, and developing strategies for restoring or overcoming resistance is ongoing and is guiding clinical studies and drug development. Causes of cellular resistance to platinums are complex and include decreased drug accumulation, increased detoxification, increased repair of DNA-platinum adducts, and increased tolerance of DNA lesions. Clinical trials are already ongoing regarding strategies involving protection of specific toxicities, decreasing intracellular glutathione (by buthionine sulfoximine), decreasing DNA repair, and introducing new analogs that are able to overcome certain forms of platinum resistance.