Modulation of Colon Carcinogenesis by Apoptosis

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In the normal cryptal cells of the intestine, cells with damaged DNA will be excluded by apoptosis. Thus, apoptosis is suggested to have an important role for the large bowel carcinogenesis. We have reported that apoptosis occurrs in the target site of large bowel carcinogenesis soon after the carcinogen exposure and cell proliferation subsequently appears almost at the same place. We also confirmed that piroxicam, a NSAID has a regressive effect on the carcinogen-induced aberrant crypt foci (ACF), and speculate that the effect is related to apoptosis. Under the present research project, we clarified, that NS-393 [N-(2-cyclohexyloxy-4-nitrophenly)methane sulfonate], a selective COX2 modifier has an inhibitory effect on azoxymethane(AOM)-induced ACF formation. It is also suggested that certain cytokines or inhibitors of protein-synthesis enzymes act as a promoter for the apoptosis, and caspase inhibitors act as an inhitor for that. Presently, we examined the modifying effects of N-tosyl-L-phenylalanylchlormethyl keton (TPCK), a protease inhibitor on the development of ACF in rats. In this study, TPCK did not clearly indicate inhibitory effects on apoptosis or the occurrence of ACF. However, this agent exhibited a potent inhibitory effect on the induction of apoptosis after AOM exposure with concurrent administration of cycloheximide, a protein-synthesis inhibitor. These evidences obtained under this research project suggest to indicate that chemical modulation of apoptosis inhibits large bowel carcinogenesis and relevant apoptosis modulators are promising preventing agents for human colorectal cancers.