K-ras point mutation is associated with enhancement by deoxycholic acid ofcolon carcinogenesis induced by azoxymethane, but not with its attenuationby all-trans-retinoic acid

The effects of deoxycholic acid (DCA) with and without all-trans-retinoic a cid (ATRA) on the incidence of colon tumors induced by azoxymethane, the in cidence of K-ras point mutation in colon tumors and the labeling index of c olon mucosa were investigated in male Wistar rats. Rats received 5 weekly i njections of 7.4 mg/kg body weight of azoxymethane, From the start of the e xperiment, all rats in 3 groups also received chow pellets containing 0.3% DCA with and without s.c. injections of 0.75 or 1.5 mg/kg body weight of AT RA every other day until the end of week 45, Oral administration of DCA sig nificantly increased the incidence of colon tumors in week 45, Concomitant use of DCA and ATRA at either dose significantly attenuated the enhancement by DCA of colon tumorigenesis. Administration of DCA significantly increas ed the incidence of K-ras point mutation in colon tumors and the labeling i ndex in the colon mucosa. Combined administration of DCA and ATRA significa ntly reduced the labeling index of colon mucosa, which was increased by DCA , but did not affect the incidence of K-ras point mutation in colon tumors. These findings suggest that DCA enhances development of colon tumors and t hat this enhancement is attenuated by ATRA, A possible mechanism of this en hancement is induction of K-ras point mutation. However, decreased cell pro liferation in the colon mucosa may be closely related to the attenuation of DCA-enhanced colon tumorigenesis, but not suppression of K-rcs point mutat ion. Int. J, Cancer 88:157-161, 2000, (C) 2000 Wiley-Liss, Inc.