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The aim of this study is to investigate the chemopreventive effects of the synthetic phenolic antioxidant 1-O-hexyl-2,3, 5-trimethylhydroquinone (HTHQ) on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colon carcinogenesis in rats after initiation with 1,2-dimethylhydrazine (DMH) in male F344 rats. Groups of 20-22, 6-week-old male F344 rats were given four subcutaneous injections of 40 mg/kg body wt of DMH during the initial 4 weeks. They were then maintained on powdered basal diet containing 0.03% PhIP alone, PhIP together with 0.5 or 0.125% HTHQ, 0.5 or 0.125% HTHQ alone or basal diet for 32 weeks. A small number (1.1 +/- 1.1/rat) of colon tumors were induced by DMH treatment alone. After initiation with DMH, the number of colon tumors was greatly increased to 8.3 +/- 5.6 by the administration of PhIP. Additional treatment with HTHQ dose-dependently decreased the multiplicity of colon adenocarcinomas to 4.9 +/- 2.8 and 2.6 +/- 1.4 with 0.125 and 0.5%, respectively. This treatment similarly reduced atypical hyperplasias of the ventral prostate. Furthermore, HTHQ significantly reduced the multiplicity of duodenal adenocarcinomas induced by DMH + PhIP or DMH alone. Immunohistochemically, HTHQ was revealed to suppress PhIP-DNA adduct formation in the epithelial cells of the colon and prostate in a separate 2 weeks experiment. The present results clearly showed that HTHQ has chemopreventive potential for PhIP-associated colon and prostate carcinogenesis. The observed inhibition may largely be due to interference with PhIP-DNA adduct formation. In addition, HTHQ has been demonstrated to inhibit duodenal carcinogenesis in the post-initiation stage.

Previous cancer chemoprevention studies have demonstrated that NSAIDs can be effective in suppressing the development of intestinal tumors. To further explore this issue, we performed cross-over chemoprevention studies using the drug piroxicam in the ApcMin mouse to evaluate the kinetics of NSAID-mediated tumor regression, the effects of genetic background and the incidence of resistance to chemoprevention. Starting at the time of weaning, C57BI/ 6J-ApcMin mice were fed either the control diet (AIN-93G) or AIN-93G plus 200 p.p.m. piroxicam. Tumor multiplicity was significantly reduced in ApcMin mice that were fed 200 p.p.m. piroxicam until 100 or 200 days of age (94.4 and 95.7% reduction in tumor number, respectively; P < 0.001 versus AIN-93G controls). When the administration of piroxicam was delayed until 100 days of age and the mice were killed at 200 days of age, tumor multiplicity was reduced by 96.2% (P < 0.001 versus controls). Alternatively, when the administration of piroxicam was suspended at 100 days of age and the mice were killed at 200 days of age, tumor multiplicity was reduced by 68.0% (P < 0.001 versus controls). Short-term drug treatment periods for ApcMin animals with established tumors revealed that the kinetics of piroxicam-induced tumor regression were rapid: >90% reduction in tumor multiplicity was observed after 1 week of treatment with 200 p.p.m. piroxicam. The distribution of residual tumors in piroxicam-treated mice suggests that tumors of the duodenum and colon were relatively resistant to chemosuppression. Treatment of interspecific hybrid ApcMin mice with 200 p.p.m. piroxicam revealed that there was a strain-related effect on chemosuppression, suggesting the existence of genetic elements which modulate NSAID chemosensitivity. Finally, whole-genome allelic loss studies showed that there were few unique chromosomal deletions in the NSAID-resistant tumors from F1 mice, implying that loss-of-function mutations secondary to Apc inactivation are not likely to account for the observed difference in chemoresistance.

The effects of simultaneous soybean trypsin inhibitor (SBTI) treatment on initiation of pancreatic carcinogenesis by N-nitrosobis(2-oxopropyl)amine (BOP) were investigated. Female Syrian golden hamsters were given five weekly s.c. injections of BOP at a dose of 10 mg/kg while being administered a diet containing 5% SBTI for 5 weeks (BOP + SBTI group). Two other groups of 30 animals each received the s.c. injections of BOP or the 5% SBTI diet for the same period, alone (BOP and SBTI groups respectively). Total numbers of pancreatic dysplastic lesions in hamsters of the BOP+SBTI group were significantly decreased as compared to the BOP group values, though the incidences of pancreatic adenocarcinomas were not significantly different. Atrophic changes were, however, more severe in the BOP group than in the BOP+SBTI group pancreatic exocrine tissue, showing that treatment with SBTI was effective for protection of acinar cells from carcinogen toxicity.