Modulation of Colon Carcinogenesis by Apoptosis

在肠的正常隐窝细胞中，具有受损DNA的细胞将通过凋亡被排除。因此，细胞凋亡在大肠癌的发生发展中起重要作用。我们曾报道大肠癌发生的靶部位在接触致癌物后不久即发生细胞凋亡，随后几乎在同一部位出现细胞增殖。我们还证实，吡罗昔康，非甾体抗炎药有一个倒退的作用，致癌剂诱导的异常隐窝灶（ACF），并推测该效果与细胞凋亡。在本研究项目下，我们阐明，NS-393 [N-（2-环己氧基-4-硝基苯基）甲烷磺酸盐]，一种选择性COX 2改性剂，对氧化偶氮甲烷（AOM）诱导的ACF形成具有抑制作用。某些细胞因子或蛋白质合成酶抑制剂可能是细胞凋亡的促进剂，而半胱天冬酶抑制剂可能是细胞凋亡的抑制剂。本实验研究了蛋白酶抑制剂N-对甲苯磺酰-L-苯丙氨酰氯甲基酮（TPCK）对大鼠ACF形成的影响。在这项研究中，TPCK没有明确表明对细胞凋亡或ACF发生的抑制作用。然而，这种药物表现出一个有效的抑制作用，诱导凋亡AOM暴露后，同时给予放线菌酮，蛋白质合成抑制剂。这些研究结果表明，化学调控细胞凋亡可以抑制大肠癌的发生，相关的凋亡调控剂有望成为大肠癌的预防药物。

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.