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Nitric Oxide–Donating Aspirin Prevents Pancreatic Cancer in a Hamster Tumor Model

¹ Division of Cancer Prevention, State University of New York at Stony Brook, Stony Brook, New York; ² Department of Surgery, Mt. Sinai School of Medicine; ³ Department of Physiology and Pharmacology, City University of New York Medical School, New York, New York; ⁴ Department of Pathology, New York Medical College, Valhalla, New York; and ⁵ Chemoprevention Branch, Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Basil Rigas, Division of Cancer Prevention, State University of New York at Stony Brook, Life Sciences Building, Room 006, Stony Brook, NY 11794-5200. Phone: 631-632-9035; Fax: 631-632-1992; E-mail: basil.rigas{at}sunysb.edu.

To evaluate the chemopreventive effect of nitric oxide–donating aspirin (NO-ASA), an ASA bearing a NO-releasing moiety, against pancreatic cancer, we studied six groups of female Syrian golden hamsters: groups 1 to 3 (n = 12 each) were given saline and groups 4 to 6 (n = 17) the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) s.c. in five weekly injections (the first, 70 mg/kg, and the remaining, 20 mg/kg each). Control and BOP-treated hamsters were fed a NO-ASA 3,000 ppm or conventional ASA 3,000 ppm or control diet for 19 weeks. Groups 1 to 3 had no tumors. Compared with the BOP/vehicle group, NO-ASA reduced the incidence (88.9%, P < 0.003) and multiplicity (94%, P < 0.05) of pancreatic cancer; ASA had no statistically significant effect. NO-ASA arrested the transition from PanIN2 to PanIN3 and carcinoma. The proliferation (proliferating cell nuclear antigen) / apoptosis (terminal deoxyribonucleotide transferase–mediated nick-end labeling) ratio of ductal cells increased with the histologic severity of the ductal lesion; NO-ASA suppressed it significantly during all stages except PanIN1A. p21^WAF1/CIP1, undetectable in normal cells, was progressively induced in neoplastic cells and suppressed by NO-ASA up to PanIN3. Nuclear factor-B activation, absent in normal tissue, increased progressively (17-fold in cancer); NO-ASA suppressed it throughout and significantly in PanIN1B and PanIN2. Cyclooxygenase-2 expression, absent during early stages, was induced 6-fold in carcinoma and suppressed by NO-ASA in PanIN3 and carcinoma. Conventional ASA had no effect on these molecular markers. Thus, NO-ASA profoundly prevented pancreatic cancer and modulated multiple molecular targets in this model system; conventional ASA had no such effects. NO-ASA merits further evaluation as a chemopreventive agent against pancreatic cancer. (Cancer Res 2006; 66(8): 4503-11)

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