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Nitric Oxide–Donating Aspirin Derivatives Suppress Microsatellite Instability in Mismatch Repair–Deficient and Hereditary Nonpolyposis Colorectal Cancer Cells

¹ Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics, The Ohio State University Comprehensive Cancer Center and Medical Center, Columbus, Ohio; ² Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; ³ Institute of Pathology, Klinikum Kassel, and TARGOS Molecular Pathology GmbH, Kassel, Germany; ⁴ Division of Cancer Prevention, State University of New York at Stony Brook, Stony Brook, New York; and ⁵ Division of Cancer Prevention, NIH/NCI/DCP, Bethesda, Maryland

Requests for reprints: Richard Fishel, Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics, The Ohio State University Comprehensive Cancer Center and Medical Center, 400 West 12th Avenue, Columbus, OH 43026. Phone: 614-292-2484; Fax: 215-503-6739; E-mail: rfishel{at}osu.edu.

Nitric oxide–donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are an emergent class of pharmaceutical derivatives with promising utility as cancer chemopreventive agents. Aspirin and sulindac have been shown to be effective in selecting for cells with reduced microsatellite instability (MSI) that is inherent in mismatch repair (MMR)–deficient hereditary nonpolyposis colorectal cancer (HNPCC) cells. The effect of NO-NSAIDs on MSI in MMR-deficient HNPCC cells is unknown. Here, we have examined genetically defined MMR-deficient murine embryo fibroblasts, murine colonocytes, and isogenic human HNPCC tumor cell lines treated with acetylsalicylic acid (aspirin; ASA) and three isomeric derivatives of NO-aspirin (NO-ASA). The MSI profiles were determined and compared with the Bethesda Criteria. We found that the ASA- and NO-ASA–treated MMR-deficient cell lines displayed a dose-dependent suppression of MSI that appeared as early as 8 weeks and gradually increased to include up to 67% of the microsatellite sequences examined after 19 to 20 weeks of continuous treatment. Residual resistance to microsatellite stabilization was largely confined to mononucleotide repeat sequences. Control (MMR-proficient) cells showed no changes in microsatellite status with or without treatment. The relative dose-dependent stabilization selection was: ortho-NO-ASA para-NO-ASA > meta-NO-ASA >> ASA. Moreover, the doses required for stabilization by the ortho- and para-NO-ASA were 300- to 3,000-fold lower than ASA. These results suggest that NO-ASA derivatives may be more effective at suppressing MSI in MMR-deficient cell lines than ASA and should be considered for chemopreventive trials with HNPCC carriers. [Cancer Res 2007;67(22):10966–75]