INHIBITION BY RETINOIC ACID OF HEPATOCARCINOGENESIS INDUCED BY N-NITROSOMORPHOLINE AND OF EXPRESSION OF MYC ONCOGENE PROTEIN IN SPRAGUE-DAWLEY RATS

The effects of all-trans-retinoic acid (RA) on hepato-carcinogenesis induced by N-nitrosomorpholine (NNM) and on the expression of myc p110 proteins were investigated in male Sprague-Dawlay rats. Rats received i.m. injections of RA twice a week and, from the beginning of the experiment, were given drinking water containing NNM for 8 weeks. Pre-neoplastic and neoplastic lesions staining positively for gamma-glutamyl transpeptidase (GGT), glutathione-S-transferase placental type (GST-P) or myc p110 protein were examined histochemically. At week 18, quantitative histological analysis showed that prolonged administration of RA resulted in a significant reduction in the number, size and volume of GGT-positive and GST-P-positive hepatic lesions. Administration of RA also caused a significant increase in the proportion of myc p110-negative lesions to the total pre-neoplastic lesions observed. Myc p110-negative lesions had a significantly lower mitotic index than myc p110-positive lesions. These findings indicate that RA inhibits hepatocarcinogenesis and suggest that this effect may be related to its influence in reducing the expression of myc gene proteins and its subsequent inhibition of cell proliferation in pre-neoplastic lesions.