Effect of retinoids on AOM-induced colon cancer in rats: modulation of cell proliferation, apoptosis and aberrant crypt foci.
Effect of retinoids on AOM-induced colon cancer in rats: modulation of cell proliferation, apoptosis and aberrant crypt foci.
复制标题
类视黄醇对 AOM 诱导的大鼠结肠癌的影响：细胞增殖、凋亡和异常隐窝病灶的调节。
DOI：
10.1093/carcin/20.2.255
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发表时间：
1999
期刊：
影响因子：
4.7
通讯作者：
Pereira,MA
中科院分区：
文献类型：
--
作者：
Zheng,Y;Kramer,PM;Lubet,RA;Steele,VE;Kelloff,GJ;Pereira,MA
我们先前已报道，维甲酸、4-羟基苯基维甲酰胺(4-HPR)和9-顺式维甲酸(RA)可预防AOM诱导的结肠肿瘤，并与2-(羧基苯基)维甲酰胺(2-CPR)一起预防异常隐窝病灶(ACF)。在本研究中，我们评估了2-CPR对AOM诱导的结肠肿瘤的作用，以及三种维甲酸对细胞凋亡和细胞增殖的影响。雄性F344大鼠分别于7周龄和8周龄时给予AOM 15 mg/kg。2-CPR(315 mg/kg)于AOM首剂服药前1周或服药后12周开始灌胃。这些大鼠继续接受2-CPR，直到第46周处死。与其他两种维甲酸对结肠癌的预防不同，2-CPR的两种给药方案都使结肠癌的产量几乎翻了一番。在腺瘤中，2-CPR、4-HPR和9-cis-RA同样有效地抑制有丝分裂活性，而只有4-hpr和9-cis-RA而不是2-cpr促进细胞凋亡。当仅在杀死4-HPR前6天给予4-HPR而不是2-CPR时，腺瘤的有丝分裂指数降低，细胞凋亡指数增加。在非受累隐窝中，与2-CPR相比，长期暴露于4-HPR和9-cis-RA降低了有丝分裂指数，并增加了凋亡指数。与我们之前的研究一致，2-CPR和4-HPR在预防ACF方面都非常有效，从第一次服用AOM前1周开始，一直持续到研究的5周。因此，与其他两种维甲酸不同，2-CPR虽然在预防ACF方面非常有效，但它增强了而不是预防了AOM诱导的结肠癌。此外，我们的结果表明，2-CPR对肿瘤产量的影响不同于4-HPR和9-cis-RA，因为与它们不同的是，它不促进细胞凋亡。
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.