Cisplatin resistance and oncogenes--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 development 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 pathways have been characterized indicating that altered expression of oncogenes that subsequently limit the formation of cisplatin-DNA adducts and activate anti-apoptotic pathways may also contribute to the resistance phenotype. Several lines of evidence suggest that expression of ras oncogenes can confer resistance to cisplatin by reducing drug uptake and increasing DNA repair; however, this is not a uniform finding. Tumor cells, in contrast to normal cells, respond to cisplatin exposure with transient gene expression to protect or repair their chromosomes. The c-fos/AP-1 complex, a master switch 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 transcription factors, modulated by protein kinase A, are also implicated in cisplatin resistance by regulating genes encoding for DNA polymerase beta and metallothionines. Furthermore, considerable evidence indicates that mutated p53 plays a significant role in the development of cisplatin resistance since several genes implicated in drug resistance and apoptosis (e.g. mismatch repair, bcl-2, high mobility group proteins, DNA polymerases alpha and beta, PCNA, and insulin-like growth factor) are known to be regulated by the p53 oncoprotein. Improved understanding of molecular factors for the development of cisplatin resistance may allow the prediction of clinical response to cisplatin-based treatment. Furthermore, the identification of oncogenes involved in cisplatin resistance has already led to in vitro approaches which successfully inactivated these genes using ribozymes or antisense oligodeoxynucleotides, 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 potential of this drug.
Dempke
W
W
Department of Internal Medicine, Martin-Luther-University, Halle/Saale, Germany. wolfram.dempke@medizin.uni-halle.de
Voigt
W
W
Grothey
A
A
Hill
B T
BT
Schmoll
H J
HJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology*; D016213:Cyclins / Q000502:physiology; D018736:DNA Adducts / Q000187:drug effects; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D015316:Genetic Therapy; D006801:Humans; D009857:Oncogenes / Q000502:physiology*
D000970:Antineoplastic Agents; D016213:Cyclins; D018736:DNA Adducts; D002945:Cisplatin