K-ras point mutation is associated with enhancement by deoxycholic acid of colon carcinogenesis induced by azoxymethane, but not with its attenuation by all-trans-retinoic acid.
The effects of deoxycholic acid (DCA) with and without all-trans-retinoic acid (ATRA) on the incidence of colon tumors induced by azoxymethane, the incidence of K-ras point mutation in colon tumors and the labeling index of colon mucosa were investigated in male Wistar rats. Rats received 5 weekly injections of 7.4 mg/kg body weight of azoxymethane. From the start of the experiment, 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 ATRA every other day until the end of week 45. Oral administration of DCA significantly 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 increased the incidence of K-ras point mutation in colon tumors and the labeling index in the colon mucosa. Combined administration of DCA and ATRA significantly 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 that this enhancement is attenuated by ATRA. A possible mechanism of this enhancement is induction of K-ras point mutation. However, decreased cell proliferation in the colon mucosa may be closely related to the attenuation of DCA-enhanced colon tumorigenesis, but not suppression of K-ras point mutation.
Narahara
H
H
Department of Gastroenterology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan. narahara@d1.dion.ne.jp
Tatsuta
M
M
Iishi
H
H
Baba
M
M
Uedo
N
N
Sakai
N
N
Yano
H
H
Ishiguro
S
S
D000284:Administration, Oral; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001397:Azoxymethane / Q000633:toxicity*; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000517:prevention & control; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000633:toxicity*; D004357:Drug Synergism; D011905:Genes, ras / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008940:Mitotic Index; D017354:Point Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D014212:Tretinoin / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D003840:Deoxycholic Acid; D014212:Tretinoin; D016283:Proto-Oncogene Proteins p21(ras); D001397:Azoxymethane