Reversal of drug resistance in human tumor xenografts by 2 '-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter

Loss of DNA mismatch repair because of hypermethylation of the hMLH1 gene p romoter occurs at a high frequency in a number of human tumors. A role for loss of mismatch repair (MMR) in resistance to a number of clinically impor tant anticancer drugs has been shown, We have investigated whether the deme thylating agent 2'-deoxy-5-azacytidine (DAC) can be used in vivo to sensiti ze MMR-deficient, drug-resistant ovarian (A2780/cp70) and colon (SW48) tumo r xenografts that are MLH1 negative because of gene promoter hypermethylati on, Treatment of tumor-bearing mice with the demethylating agent DAC at a n ontoxic dose induces MLH1 expression. Re-expression of MLH1 is associated w ith a decrease in hMLH1 gene promoter methylation. DAC treatment alone has no effect on the growth rate of the tumors. However, DAC treatment sensitiz es the xenografts to cisplatin, carboplatin, temozolomide, and epirubicin, Sensitization is comparable with that obtained by reintroduction of the hML H1 gene by chromosome 3 transfer. Consistent with loss of MMR having no eff ect on sensitivity in vitro to Taxol, DAC treatment has no effect on the Ta xol sensitivity of the xenografts, DAC treatment does not sensitize xenogra fts of HCT116, which lacks MMR because of hMLH1 mutation. Because there is emerging data on the role of loss of 1MMR in clinical drug resistance, DAC could have a role in increasing the efficacy of chemotherapy for patients w hose tumors lack MLH1 expression because of hMLH1 promoter methylation,.