Journal Article

Effect of retinoids on AOM-induced colon cancer in rats: modulation of cell proliferation, apoptosis and aberrant crypt foci

Ye Zheng, Paula M. Kramer, Ronald A. Lubet, Vernon E. Steele, Gary J. Kelloff and Michael A. Pereira

in Carcinogenesis

Volume 20, issue 2, pages 255-260
Published in print February 1999 | ISSN: 0143-3334
Published online February 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.2.255
Effect of retinoids on AOM-induced colon cancer in rats: modulation of cell proliferation, apoptosis and aberrant crypt foci

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We have previously reported that the retinoids, 4-(hydroxyphenyl)retinamide (4-HPR) and 9-cis-retinoic acid (RA) prevented azoxymethane (AOM)-induced colon tumors and along with 2-(carboxyphenyl)retinamide (2-CPR) prevented aberrant crypt foci (ACF). In this study, we evaluated the effect of 2-CPR on AOM-induced colon tumors and the effect of the three retinoids on apoptosis and cell proliferation. Male F344 rats were administrated 15 mg/kg AOM at weeks 7 and 8 of age. 2-CPR (315 mg/kg) was administered in the diet starting either 1 week before or at week 12 after the first dose of AOM. The rats continued to receive the 2-CPR until killed at week 46. Unlike the demonstrated prevention of colon cancer by the other two retinoids, both dosing schedules of 2-CPR resulted in an approximate doubling of the yield of colon tumors. In adenomas, 2-CPR, 4-HPR and 9-cis-RA were equally effective in reducing mitotic activity, while only 4-HPR and 9-cis-RA but not 2-CPR enhanced apoptosis. When administered for only the 6 days prior to killing 4-HPR but not 2-CPR decreased the Mitotic Index and increased the Apoptotic Index in adenomas. In non-involved crypts, chronic exposure to 4-HPR and 9-cis-RA in contrast to 2-CPR reduced the Mitotic Index and enhanced the Apoptotic Index. In concurrence with our previous study, both 2-CPR and 4-HPR were very potent in preventing ACF when administered in the diet starting 1 week before the first dose of AOM and continuing for the 5 weeks of the study. Hence, unlike the other two retinoids, 2-CPR, although very potent in preventing ACF, enhanced rather than prevented AOM-induced colon cancer. Furthermore, our results suggest that the effect of 2-CPR on tumor yield is different from 4-HPR and 9-cis-RA because, unlike them, it does not enhance apoptosis.

Keywords: ACF, aberrant crypt foci; AOM, azoxymethane; 2-CPR, 2-(carboxyphenyl)retinamide; 4-HPR, 4-(hydroxyphenyl)retinamide; PCNA, proliferating cell nuclear antigen; 6-PHITC, 6-phenylhexyl isothiocyanate; RA, retinoic acid.

Journal Article.  4489 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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