Data from Aspirin and Low-Dose Nitric Oxide–Donating Aspirin Increase Life Span in a Lynch Syndrome Mouse Model

• DOI: 10.1158/1940-6207.c.6544149.v1
• Publication Date: 2024-03-12T15:33:16Z
• Authors: Michael A. Mcilha...; Jessica Tyler; Laura A. Kerepesi; Tina Bocker-Edmon...; Melanie H. Kucher...; Winfried Edelmann; Raju Kucherlapati; Levy Kopelovich; Richard Fishel

<div>Abstract<p>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. <i>Cancer Prev Res; 4(5); 684–93. ©2011 AACR</i>.</p></div>