Do Fanconi anemia genes control cell response to cross-linking agents by modulating cytochrome P-450 reductase activity?

The Fanconi anemia (FA) genes play an important role in maintaining chromos omal stability and the defense of mammalian cells against cross-linking age nts, such as cisplatin and mitomycin C (MMC). Cells derived from FA patient s display a characteristic hypersensitivity toward cross-linking agents. De spite great progression in our understanding of the mechanisms that protect cells against these potent anti-cancer drugs, the specific roles of FA gen e products in these processes have not been delineated. Recent studies have shown that the FA group C gene product, FANCC, can bind to and regulate th e activity of cytochrome P450-reductase (P450R), an enzyme involved in the bioactivation of MMC. In this mini-review, this finding is placed in the co ntext of complex mechanisms involved in the bioreductive activation of MMC acid the hypersensitivity of FA cells to MMC. Although it would be prematur e to attribute the FA phenotype wholly to an abnormal activation of MMC, th e regulation of P450R by FANCC suggests a novel link between one or more FA gene products, the cellular oxidative state, and the response to chemother apeutic agents.