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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.
AuthorsMichael A McIlhatton, Jessica Tyler, Laura A Kerepesi, Tina Bocker-Edmonston, Melanie H Kucherlapati, Winfried Edelmann, Raju Kucherlapati, Levy Kopelovich, Richard Fishel
JournalCancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 4 Issue 5 Pg. 684-93 (May 2011) ISSN: 1940-6215 [Electronic] United States
PMID21436383 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • nitroxy-butyl-acetylsalicylic acid
  • Nitric Oxide
  • Aspirin
Topics
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
  • Aspirin (analogs & derivatives, therapeutic use)
  • Base Pair Mismatch (drug effects)
  • Colorectal Neoplasms, Hereditary Nonpolyposis (drug therapy)
  • DNA Repair
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Longevity (drug effects)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microsatellite Instability
  • Nitric Oxide (metabolism)
  • Survival Rate

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