| First Author | McIlhatton MA | Year | 2011 |
| Journal | Cancer Prev Res (Phila) | Volume | 4 |
| Issue | 5 | Pages | 684-93 |
| PubMed ID | 21436383 | Mgi Jnum | J:325939 |
| Mgi Id | MGI:7287927 | Doi | 10.1158/1940-6207.CAPR-10-0319 |
| Citation | McIlhatton MA, et al. (2011) Aspirin and low-dose nitric oxide-donating aspirin increase life span in a Lynch syndrome mouse model. Cancer Prev Res (Phila) 4(5):684-93 |
| abstractText | 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. |
