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Experimental Therapeutics |
Department of Medicine and the Cancer Center, University of California, San Diego, La Jolla, California 92093-0058
This study examined how the DNA mismatch repair (MMR) system and p53 interact to maintain genomic integrity in the presence of the mutagenic stress induced by cisplatin (DDP). Sensitivity to the cytotoxic and mutagenic effect of DDP was assessed using a panel of sublines of the MMR-deficient HCT116 colon carcinoma cells in which MMR function had been restored by transfer of a copy of MLH1 on chromosome 3 or in which p53 function had been disabled by expression of HPV-16 E6. Loss of p53 function by expression of E6 in MMR-proficient HCT116+ch3 cells conferred only 1.1–2.0-fold resistance to a panel of commonly used chemotherapeutic agents, whereas disruption of p53 in MMR-deficient HCT116 cells resulted in substantial levels of resistance to some agents (paclitaxel, 1.9-fold; gemcitabine, 2.7-fold; 6-thioguanine, 3.3-fold; and etoposide, 4.4-fold) but sensitization to other agents (topotecan, 2.5-fold; and DDP, 3.3-fold). Loss of MMR or p53 alone had only a minor effect on sensitivity to the mutagenic effect of DDP as measured by the appearance of variants resistant to 6-thioguanine, etoposide, topotecan, gemcitabine, and paclitaxel in the population 10 days later (1.0–2.4-fold), whereas loss of both p53 and MMR had a more profound effect (1.7–6.5-fold). Loss of both p53 and MMR increased the basal frequency insertion/deletion mutations detected by a shuttle vector-based assay to a greater extent than loss of either alone. In association with DDP-induced injury, loss of p53 or MMR alone resulted in 1.2- and 1.7-fold more mutations, whereas loss of both resulted in a 5.1-fold increase in mutant frequency. Examination of the impact of loss of p53 and/or MMR on the DDP-induced cell cycle checkpoint activation, p53 induction, ability of the cell to tolerate adducts in its DNA, and the rate of disappearance of platinum from genomic DNA indicated the effects of the loss of p53 and/or MMR on all of these parameters, suggesting a multifactorial etiology for the changes in sensitivity to the cytotoxic and mutagenic effects of DDP. These results indicate that p53 and MMR can cooperate to control sensitivity to the cytotoxic effect of DDP and to limit its mutagenic potential in the colon cancer cells.
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