ASPIRIN SUPPRESSES THE MUTATOR PHENOTYPE ASSOCIATED WITH HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER BY GENETIC SELECTION

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known cancer pr eventives, which have been largely attributed to their antiproliferati ve and apoptosis-inducing activities. In this study, we show that micr osatellite instability (MSI) in colorectal cancer cells deficient for a subset of the human mismatch repair (MMR) genes (hMLH1, hMSH2, and h MSH6), is markedly reduced during exposure to aspirin or sulindac [or Clinoril, which is chemically related to indomethacin (Indocin)], This effect was reversible, time and concentration dependent, and appeared independent of proliferation rate and cyclooxygenase function, In con trast, the MSI phenotype of a hPMS2-deficient endometrial cancer cell line was unaffected by aspirin/sulindac. We show that the MSI reductio n in the susceptible MMR-deficient cells was confined to nonapoptotic cells, whereas apoptotic cells remained unstable and were eliminated f rom the growing population. These results suggest that aspirin/sulinda c induces :a genetic selection for microsatellite stability in a subse t of MMR-deficient cells and may provide an effective prophylactic the rapy for hereditary nonpolyposis colorectal cancer kindreds where alte ration of the hMSH2 and hMLH1 genes are associated with the majority o f cancer susceptibility cases.