Cisplatin resistance and oncogene - a review

Cisplatin is among the most widely used broadly active cytotoxic anticancer drugs; however, its clinical efficacy is often limited by primary or the d evelopment of secondary resistance. Several mechanisms have been implicated in cisplatin resistance, including reduced drug uptake, increased cellular thiol/folate levels and increased DNA repair. More recently, additional pa thways have been characterized indicating that altered expression of oncoge nes that subsequently limit the formation of cisplatin-DNA adducts and acti vate anti-apoptotic pathways may also contribute to the resistance phenotyp e. Several lines of evidence suggest that expression of ras oncogenes can c onfer resistance to cisplatin by reducing drug uptake and increasing DNA re pair; however, this is not a uniform finding. Tumor cells, in contrast to n ormal cells, respond to cisplatin exposure with transient gene expression t o protect or repair their chromosomes. The c-fos/AP-1 complex, a master swi tch for turning on other genes in response to DNA-damaging agents, has been shown to play a major role in cisplatin resistance. In addition, AP-2 tran scription factors, modulated by protein kinase A, are also implicated in ci splatin resistance by regulating genes encoding for DNA polymerase beta and metallothionines. Furthermore, considerable evidence indicates that mutate d p53 plays a significant role in the development of cisplatin resistance s ince several genes implicated in drug resistance and apoptosis (e.g. mismat ch repair, bcl-2, high mobility group proteins, DNA polymerases alpha and b eta, PCNA, and insulin-like growth factor) are known to be regulated by the p53 oncoprotein. Improved understanding of molecular factors for the devel opment of cisplatin resistance may allow the prediction of clinical respons e to cisplatin-based treatment. Furthermore, the identification of oncogene s involved in cisplatin resistance has already led to in vitro approaches w hich successfully inactivated these genes using ribozymes or antisense olig odeoxynucleotides, thus restoring cisplatin sensitivity. It is conceivable that these strategies, once transferred to a clinical setting, may have the potential to enhance the efficacy of cisplatin against a great variety of malignancies and thus more fully exploit the antineoplastic and curative po tential of this drug. [(C) 2000 Lippincott Williams & Wilkins.].