Fukushima S, Shibata M A, Hirose M, Kato T, Tatematsu M, Ito N
First Department of Pathology, Nagoya City University Medical School.
Jpn J Cancer Res. 1991 Jul;82(7):784-92. doi: 10.1111/j.1349-7006.1991.tb02703.x.
The combined effects of low doses of various carcinogens and carcinogenesis modifiers on tumor development were investigated by using a wide-spectrum organ carcinogenesis model in F344 rats. These agents were administered as three groups: (1) a group of known hepatocarcinogens; (2) a group of nitroso compounds having various target organ specificities; and (3) a group of antioxidants having various inhibiting or enhancing activities depending on the target organ. Doses were used which were generally below the known effective level for the individual chemical. These groups of chemicals were administered with or without prior administration of N-diethylnitrosamine (100 mg/kg body wt., i.p.), N-methylnitrosourea (4 x 20 mg/kg body wt., i.p.) and dihydroxy-di-N-propylnitrosamine (0.1% in drinking water for 2 weeks). The hepatocarcinogen group in combination with various nitroso compounds increased the incidences of liver hyperplastic nodules and hepatocellular carcinomas. In contrast, incidences were clearly reduced when the hepatocarcinogens and/or the nitroso compounds were administered in combination with the antioxidants. For the urinary bladder, the combination with nitroso compounds and antioxidants enhanced cancer development, and the addition of hepatocarcinogens further increased tumorigenesis. For the glandular stomach, additive effects on the numbers of pepsinogen isozyme 1-altered pyloric glands, a putative preneoplastic lesion, were produced by the combination treatment of antioxidants and the nitroso compounds. No synergistic effects on tumor development were seen in other organs. The results of the present study demonstrated that combinations of various compounds at low doses can additively or synergistically exert either enhancing or inhibitory effects on the development of preneoplastic and neoplastic lesions in different organs in a single model having a wide spectrum of organ effects.
利用F344大鼠的广谱器官致癌模型，研究了低剂量各种致癌物和致癌作用调节剂对肿瘤发生的联合作用。这些试剂分为三组给药：（1）一组已知的肝癌致癌物；（2）一组具有不同靶器官特异性的亚硝基化合物；（3）一组根据靶器官具有不同抑制或增强活性的抗氧化剂。使用的剂量通常低于各化学物质已知的有效水平。这些化学物质组在给予或不给予N-二乙基亚硝胺（100mg/kg体重，腹腔注射）、N-甲基亚硝基脲（4×20mg/kg体重，腹腔注射）和二羟基二-N-丙基亚硝胺（饮用水中0.1%，持续2周）的情况下给药。肝癌致癌物组与各种亚硝基化合物联合使用增加了肝脏增生性结节和肝细胞癌的发生率。相反，当肝癌致癌物和/或亚硝基化合物与抗氧化剂联合使用时，发生率明显降低。对于膀胱，与亚硝基化合物和抗氧化剂联合使用促进了癌症发展，添加肝癌致癌物进一步增加了肿瘤发生。对于腺胃，抗氧化剂和亚硝基化合物联合治疗对胃蛋白酶原同工酶1改变的幽门腺数量（一种假定的癌前病变）产生了相加作用。在其他器官中未观察到对肿瘤发生的协同作用。本研究结果表明，在一个具有广泛器官效应的单一模型中，低剂量各种化合物的组合可以对不同器官的癌前和肿瘤性病变的发展产生相加或协同的增强或抑制作用。
