Modulation of Colon Carcinogenesis by Apoptosis

在正常的肠道隐窝细胞中，DNA受损的细胞将被凋亡排除在外。因此，细胞凋亡在大肠癌的发生发展中起着重要作用。我们已经报道，在致癌物暴露后不久，大肠癌变的靶点发生了细胞凋亡，随后细胞增殖几乎出现在同一位置。我们还证实了非甾体类抗炎药吡罗昔康对致癌物诱导的异常隐窝病灶(ACF)具有消退作用，并推测其作用与细胞凋亡有关。在本研究项目中，我们明确了选择性COX2修饰剂NS-393[N-(2-环己氧基-4-硝基苯基)甲烷磺酸盐]对偶氮甲烷(AOM)诱导的ACF的形成具有抑制作用。也有人认为，某些细胞因子或蛋白质合成酶的抑制剂对细胞凋亡起促进作用，而caspase抑制剂则对此起抑制作用。目前，我们观察了N-对甲苯磺酰-L-苯丙氨酰氯甲基酮(TPCK)对大鼠ACF发生发展的影响。在这项研究中，TPCK没有明确地表明对细胞凋亡或ACF的发生的抑制作用。然而，这种药物在AOM暴露后同时给予蛋白质合成抑制剂放线菌酮后，对诱导细胞凋亡有很强的抑制作用。本研究获得的这些证据表明，细胞凋亡的化学调控抑制了结直肠癌的发生，相关的细胞凋亡调节剂有望成为人类结直肠癌的预防药物。

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.