Molecular basis of cis-diamminedichloroplatinum(II) resistance: a review

Cisplatin is one of the most widely used chemotherapeutic agents. However, at sublethal concentrations, resistance of cells to the drug occasionally arise, which greatly limits its effectiveness in cancer therapy. In this review, the mechanisms of acquired resistance to cisplatin are elucidated. Numerous mechanisms potentially contributing to clinical cisplatin resistance have been identified, including changes in membrane permeability, detoxification pathways and the ability to remove cytotoxic lesions from DNA. Changes triggered by cisplatin selection in the resistant phenotype involve a secondary layer of complexity that may include alterations in: 1) oncogene and protein kinase signal transduction pathways: 2) growth factor and hormone responsiveness; 3) chromosome structure and gene expression; 4) ion transport; 5) thymidilate metabolism; and 6) nutrient transport and utilization. It is likely that all of these changes are part of an interconnected, multifarious response to cisplatin selection. Which of these biochemical changes come to predominate may depend on the type of cell and, particularly, on the selection procedure. In general, chronic, long-term exposure to increasing concentrations of cisplatin seems to lead to permanent elevations in the levels of the nucleophiles glutathione and metallothionein. Pulsed administration of cisplatin once a week leads to changes in folate metabolism and oncogene expression, while acute administration of cisplatin once a month leads to defects in drug accumulation. However, the environment of a tumor is remarkably different from the environment of tumor cells in culture (nutrient, growth factor and hormone availability; pH; intercellular communication; and oxygenation state). In addition, the various oncogene and protein kinase signal transduction pathways are likely to be featured differently in these two environments. In contrast to the sublethal concentrations of cisplatin used in the selection of resistance phenotype a lethal concentration of cisplatin may generate DNA adducts in cells, which cause G2 arrest of the cell cycle and subsequently lead to apoptosis. Recently, excitement in this field arose from the findings that cisplatin-DNA adducts bind several cellular proteins, termed cisplatin-damaged-DNA recognition proteins, including some that enhance survival of the cells by mediating DNA repair and others that hasten their death by conferring sensitivity to the drug.