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-kappaB 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.