Steffensen I L, Paulsen J E, Alexander J
National Institute of Public Health, Department of Environmental Medicine, Oslo, Norway.
Carcinogenesis. 1995 Dec;16(12):2981-8. doi: 10.1093/carcin/16.12.2981.
Aberrant crypt foci (ACF) consisting of one more single aberrant crypts (AC) are putative preneoplastic lesions that have been proposed as intermediate biomarkers for colon cancer. Using ACF as the end-point we have studied the effects of two different classes of colon carcinogens, 1,2-dimethylhydrazine dihydrochloride (DMH; 10 or 20 mg/kg body wt/injection) or its metabolite azoxymethane (AOM; 5 mg/kg) and 3,2'dimethyl-4- aminobiphenyl hydrochloride (DMAB; 50 mg/kg) in F344 and Lewis rats. Each carcinogen was given alone or DMH/AOM and DMAB were given in combination in either alternating or successive order in multiple doses. Each compound given alone induced ACF in both rat strains and the effect was most pronounced in the F344 rats. DMAB, not previously tested for ability to induce ACF in rats, was clearly less potent than DMH or AOM. The highest number of ACF was found distally in the colon, independent of treatment or rat strain. Surprisingly, DMAB markedly decreased the carcinogenic effect of DMH, evaluated both as numbers of ACF and AC per colon, as well as number of ACF with four or more AC, when both classes of carcinogens were given alternately. A more pronounced reduction was found in F344 rats than in Lewis rats, being 75-77% and 64-68% respectively with the highest DMH dose. The same tendency was found with successive exposure to DMAB followed by DMH or AOM. These differences in timing of exposure and the different metabolic pathways used by the two classes of carcinogens make a metabolic interaction unlikely as the reason for the antagonistic effect of DMAB on DMH or AOM. The type of standard diet used was found to influence the induction of ACF by the colon carcinogen DMH.
由一个或多个单个异常隐窝（AC）组成的异常隐窝灶（ACF）是假定的癌前病变，已被提议作为结肠癌的中间生物标志物。以ACF为终点，我们研究了两种不同类型的结肠致癌物对F344和Lewis大鼠的影响，这两种致癌物分别是二盐酸1,2-二甲基肼（DMH；10或20mg/kg体重/注射）或其代谢产物偶氮甲烷（AOM；5mg/kg）以及盐酸3,2'-二甲基-4-氨基联苯（DMAB；50mg/kg）。每种致癌物单独给药，或者DMH/AOM和DMAB以交替或连续的顺序联合多次给药。每种单独给药的化合物在两种大鼠品系中均诱导出了ACF，且在F344大鼠中的效果最为明显。之前未测试过在大鼠中诱导ACF能力的DMAB，其效力明显低于DMH或AOM。在结肠远端发现的ACF数量最多，与治疗方式或大鼠品系无关。令人惊讶的是，当两种致癌物交替给药时，DMAB显著降低了DMH的致癌作用，无论是以每结肠的ACF数量和AC数量来评估，还是以具有四个或更多AC的ACF数量来评估。在F344大鼠中发现的降低更为明显，最高DMH剂量时分别为75 - 77%和64 - 68%。在连续暴露于DMAB后再暴露于DMH或AOM时也发现了相同的趋势。两种致癌物暴露时间的差异以及它们所使用的不同代谢途径，使得代谢相互作用不太可能是DMAB对DMH或AOM产生拮抗作用的原因。研究发现所使用的标准饮食类型会影响结肠致癌物DMH对ACF的诱导。
