Effect of post-initiation induction of NQO1 by oltipraz on AOM induced colon tumor formation in Sprague-Dawley rats
Authors: Kosala Sivananthan, Ranjana P. Bird, Andrew W. Maksymiuk, Georgia Lefas, Asher Begleiter
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2476 

Phase II detoxifying enzymes like NADP(H):quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GST) and UDP-glucuronyltransferases (UGT) may prevent carcinogen-induced cancers. Inducers of phase II detoxifying enzymes have been shown to inhibit carcinogen induced colon tumors in rat and mouse models, but the role of NQO1 in these effects was not clearly defined. We showed that oltipraz fed to Sprague-Dawley rats prior to treatment with a colon carcinogen increased NQO1 activity in the colons, without increasing GST or UGT activities, and decreased the number of aberrant crypt foci (ACF) in the colons of these rats. This was the first direct evidence that induction of NQO1 alone can inhibit initiation of colon carcinogenesis. Since oltipraz selectively induced NQO1 in these Sprague-Dawley rats without inducing other phase II detoxifying enzymes, this represents a unique model to study the role of NQO1 in colon carcinogenesis without interference from other phase II enzymes. Previous studies have shown that post-initiation administration of phase II enzyme inducers can also inhibit colon tumor formation in rats. Using the oltipraz fed Sprague-Dawley rat model, we investigated whether selective induction of NQO1 by oltipraz after treatment with the colon carcinogen azoxymethane (AOM) could also inhibit colon tumor formation. Rats were injected with 15 mg/kg AOM weekly for 2 weeks and then were fed control diet or oltipraz diet (control diet containing 200 ppm oltipraz) for 29 weeks. NQO1 activity was increased 2-fold in the colons of rats fed oltipraz diet compared with rats fed control diet, but the oltipraz diet did not increase GST or UGT activities. Rats fed oltipraz diet had 58% fewer ACF than control fed rats at 12 weeks after AOM treatment (p<0.001). However, there was no significant difference in the distribution of crypt multiplicities in the two groups. The frequency of microadenomas in oltipraz fed rats after 29 weeks was 1.07 ± 0.15/rat, while that in control fed rats was 1.87 ± 0.23/rat and this difference was statistically significant (p<0.003). The tumor frequency at 29 weeks was 0.37 ± 0.08/rat in rats fed oltipraz diet and 0.47 ± 0.09/rat in rats fed control diet, while the proportion of animals that developed colon tumors was 0.30 ± 0.05 in oltipraz fed rats and 0.37 ± 0.06 in control fed rats. Although the oltipraz fed rats had a lower tumor frequency and a lower tumor incidence than control fed rats the differences were not statistically significant. The median tumor volume was 432 mm3 in oltipraz fed rats and 219 mm3 in control fed rats. These results suggest that post-initiation induction of NQO1 can inhibit the early stages of colon carcinogenesis, but that this may not inhibit actual tumor formation. In addition, NQO1 induction may promote the growth of tumors once they have developed. (Supported by the Canadian Institutes of Health Research and CancerCare Manitoba Foundation)