title: Aspirin and low-dose nitric oxide-donating aspirin increase life span in a Lynch syndrome mouse model.
abstract: 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.
authors: Department of Molecular Virology, Immunology & Medical Genetics, Ohio State University, Columbus, OH 43210, USA.
authors: Michael A
authors: MA
authors: McIlhatton
authors: Jessica
authors: J
authors: Tyler
authors: Laura A
authors: LA
authors: Kerepesi
authors: Tina
authors: T
authors: Bocker-Edmonston
authors: Melanie H
authors: MH
authors: Kucherlapati
authors: Winfried
authors: W
authors: Edelmann
authors: Raju
authors: R
authors: Kucherlapati
authors: Levy
authors: L
authors: Kopelovich
authors: Richard
authors: R
authors: Fishel
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001241:Aspirin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D020137:Base Pair Mismatch / Q000187:drug effects; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000188:drug therapy*; D004260:DNA Repair; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D008136:Longevity / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053842:Microsatellite Instability; D009569:Nitric Oxide / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C098312:nitroxy-butyl-acetylsalicylic acid; D009569:Nitric Oxide; D001241:Aspirin