Nonsteroidal anti-inflammatory drugs (
NSAID) appear to be effective
cancer chemopreventives. Previous cellular studies showed that
aspirin (
acetylsalicylic acid: ASA) and
nitric oxide-donating ASA (
NO-ASA) suppressed
microsatellite instability (MSI) in mismatch repair (MMR)-deficient cells linked to the common
cancer predisposition syndrome
hereditary nonpolyposis colorectal cancer or
Lynch syndrome (LS/HNPCC), at doses 300- to 3,000-fold less than ASA. Using a mouse model that develops MMR-deficient intestinal
tumors that appear pathologically identical to LS/HNPCC, we show that ASA (400 mg/kg) and low-dose
NO-ASA (72 mg/kg) increased life span by 18% to 21%. We also note a trend where ASA treatment resulted in intestinal
tumors with reduced high MSI (H-MSI) and increased low MSI (L-MSI) as defined by the Bethesda Criteria. Low-dose
NO-ASA had a minimal effect on MSI status. In contrast to previous studies, high-dose
NO-ASA (720/1,500 mg/kg) treatments increased
tumor burden, decreased life span, and exacerbated MSI uniquely in the LS/HNPCC mouse model. These results suggest that MMR-deficient tissues/mice may be specifically sensitive to intrinsic pharmacokinetic features of this
drug. It is likely that long-term treatment with ASA may represent a chemopreventive option for LS/HNPCC patients. Moreover, as low-dose
NO-ASA shows equivalent life span increase at 10-fold lower doses than ASA, it may have the potential to significantly reduce the gastropathy associated with long-term ASA treatment.