Platinum drug action and resistance
Hector, Suzanne M
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Platinum (Pt) drugs such as oxaliplatin and cisplatin are important in the treatment of cancer; however their clinical use is limited by the development of resistance. Pt drug cytotoxicity is mainly attributed to the formation of Pt-DNA adducts which interfere with replication and transcription, leading to apoptotic cell death. Using cell lines sensitive and resistant to either oxaliplatin or cisplatin, the goal of these studies is to further characterize Pt drug action and resistance. Our studies show that in general, resistance to oxaliplatin and cisplatin is quite similar and appears mainly due to decreased intracellular drug accumulation, decreased Pt-DNA adducts and increased drug detoxification by glutathione.Gene expression profiling of A2780 ovarian carcinoma cells treated with either oxaliplatin or cisplatin was carried out in order to gain further insight into the mechanisms of Pt drug cytotoxicity. These studies revealed changes in the expression of hundreds of genes, including genes related to DNA repair, cell cycle progression, apoptosis, and various metabolic pathways. Among the most potently induced genes by both drugs was spermidine/spermine N 1 acetyltransferase (SSAT), a key enzyme in polyamine catabolism. Polyamines are essential for cell growth and their depletion by induction of SSAT results in cell growth inhibition and apoptosis, indicating that polyamine catabolism may play a role in the cytotoxic action of Pt drugs. Though SSAT induction by oxaliplatin occurs mainly at the level of mRNA, when combined with the clinically relevant polyamine analog N 1 , N 11 -diethylnorspermine (DENPSM) there are synergistic increases in both SSAT mRNA and activity with subsequent depletion of polyamine pools. Additionally, we have shown that low dose DENSPM enhances growth inhibition of A2780 cells by oxaliplatin. Using oxaliplatin resistant variants of A2780 cells, we examined the effects of the oxaliplatin/DENSPM combination on SSAT induction in these cells. These studies revealed that the degree of SSAT induction by the oxaliplatin/DENSPM combination is inversely related to resistance to oxaliplatin. We also demonstrate that induction of SSAT mRNA and activity by oxaliplatin/DENSPM is not specific to A2780 cells, but is demonstrable in a number of other cell lines. In conclusion, these studies indicate that polyamine catabolism may play a role in Pt drug cytotoxicity and resistance and that with appropriate in vitro and in vivo optimization the oxaliplatin/DENSPM combination may have therapeutic potential in the clinical setting.