Aspirin and low-dose nitric oxide-donating aspirin increase life span in a Lynch syndrome mouse model

Michael A. Mcilhatton, Jessica Tyler, Laura A. Kerepesi, Tina Bocker-Edmonston, Melanie H. Kucherlapati, Winfried Edelmann, Raju Kucherlapati, Levy Kopelovich, Richard Fishel

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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.

Original languageEnglish (US)
Pages (from-to)684-693
Number of pages10
JournalCancer Prevention Research
Volume4
Issue number5
DOIs
StatePublished - May 2011

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Hereditary Nonpolyposis Colorectal Neoplasms
Microsatellite Instability
Aspirin
Nitric Oxide
DNA Mismatch Repair
Neoplasms
Therapeutics
Tumor Burden
Pharmaceutical Preparations
Anti-Inflammatory Agents
Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mcilhatton, M. A., Tyler, J., Kerepesi, L. A., Bocker-Edmonston, T., Kucherlapati, M. H., Edelmann, W., ... Fishel, R. (2011). Aspirin and low-dose nitric oxide-donating aspirin increase life span in a Lynch syndrome mouse model. Cancer Prevention Research, 4(5), 684-693. https://doi.org/10.1158/1940-6207.CAPR-10-0319

Aspirin and low-dose nitric oxide-donating aspirin increase life span in a Lynch syndrome mouse model. / Mcilhatton, Michael A.; Tyler, Jessica; Kerepesi, Laura A.; Bocker-Edmonston, Tina; Kucherlapati, Melanie H.; Edelmann, Winfried; Kucherlapati, Raju; Kopelovich, Levy; Fishel, Richard.

In: Cancer Prevention Research, Vol. 4, No. 5, 05.2011, p. 684-693.

Research output: Contribution to journalArticle

Mcilhatton, MA, Tyler, J, Kerepesi, LA, Bocker-Edmonston, T, Kucherlapati, MH, Edelmann, W, Kucherlapati, R, Kopelovich, L & Fishel, R 2011, 'Aspirin and low-dose nitric oxide-donating aspirin increase life span in a Lynch syndrome mouse model', Cancer Prevention Research, vol. 4, no. 5, pp. 684-693. https://doi.org/10.1158/1940-6207.CAPR-10-0319
Mcilhatton, Michael A. ; Tyler, Jessica ; Kerepesi, Laura A. ; Bocker-Edmonston, Tina ; Kucherlapati, Melanie H. ; Edelmann, Winfried ; Kucherlapati, Raju ; Kopelovich, Levy ; Fishel, Richard. / Aspirin and low-dose nitric oxide-donating aspirin increase life span in a Lynch syndrome mouse model. In: Cancer Prevention Research. 2011 ; Vol. 4, No. 5. pp. 684-693.
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