IN-VITRO AND IN-VIVO RESISTANCE TO CISPLATIN IN CELLS THAT HAVE LOST DNA MISMATCH REPAIR

In vitro studies have shown that loss of DNA mismatch repair due to la ck of either hMSHZ or hMLH1 activity results in Low-level resistance t o cisplatin but not to oxaliplatin, an analogue that produces a differ ent type of DNA adduct. No information is currently available on wheth er this low-level resistance is sufficient to result in enrichment of mismatch repair-deficient cells during drug exposure in vitro or to ac count for clinical failure of treatment in vivo. Mixed populations of cells containing a minority of DNA mismatch repair-deficient cells con stitutively expressing green fluorescence protein were exposed repeate dly in vitro to cisplatin and oxaliplatin, Treatment with cisplatin re sulted in a gradual enrichment for DNA mismatch repair-deficient cells , whereas treatment with oxaliplatin did not, MSH2(-/-) and MSH2(+/+) embryonic stem cells were established as xenografts in athymic nude mi ce, Animals were treated 48 h after tumor implantation with a single L D10 dose of either cisplatin or oxaliplatin, MSH2(-/-) tumors were sig nificantly less responsive to cisplatin than MSH2(+/+) tumors, whereas there was no difference in sensitivity to oxaliplatin. These results demonstrate that the degree of cisplatin resistance conferred by loss of DNA mismatch repair is sufficient to produce both enrichment of mis match repair-deficient cells during treatment ill vitro and a large di fference in clinical responsiveness in vivo. The results identify loss of DNA mismatch repair as a mechanism of resistance to cisplatin but not oxaliplatin.