Diwan B A, Lubet R A, Ward J M, Hrabie J A, Rice J M
Biological Carcinogenesis and Development Program, Program Resources, Inc./DynCorp, Frederick, MD.
Carcinogenesis. 1992 Oct;13(10):1893-901. doi: 10.1093/carcin/13.10.1893.
The tumor-promoting and carcinogenic effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in the liver and in other organs were quantified and compared to those of phenobarbital (PB) in two inbred strains of mice (C57BL/6NCr, DBA/2NCr) and in F344/NCr rats initiated at 5 weeks of age with N-nitrosodiethylamine (NDEA; 90 mg/kg in mice, 75 mg/kg in rats). Two weeks later animals were placed on a regimen of TCPOBOP once every 2 weeks (administered i.p. or i.g.) or on a diet containing 500 p.p.m. PB as a positive control for the duration of the experiment. Mice were administered TCPOBOP (3.0 mg/kg/dose) for 30 weeks followed by control diet, while rats were given the TCPOBOP regimen (3.0 or 30 mg/kg/dose) for the full 78 weeks of the experiment. TCPOBOP was a complete carcinogen and an extremely potent promoter in both strains of mice, particularly the DBA strain in which NDEA followed by TCPOBOP (i.p.) resulted in death of all the animals within 30 weeks from multiple hepatocellular tumors. TCPOBOP alone induced 100% tumor incidence in DBA mice within 60 weeks. In addition, in both strains of mice, a high proportion of those animals with liver tumors had metastases to the lungs. In contrast, TCPOBOP was ineffective as a liver tumor promoter in F344 rats at even 10 times the dose administered to mice. Interestingly however, TCPOBOP, when given subsequent to NDEA, caused a significant increase in nasal cavity tumors in F344 rats. PB was an effective liver tumor promoter in male DBA mice and male F344 rats, but was relatively ineffective as a promoter in C57 mice. When tumor-promoting activity and induction of cytochrome P450 IIB1 were compared, good agreement between these two parameters was observed. PB was an effective inducer of P450 IIB1 in the rats and in both strains of mice and a potent liver tumor promoter in both DBA mice and F344 rats, whereas TCPOBOP was a potent inducer and tumor promoter in both strains of mice but was negligibly effective as either an inducer or a promoter in F344 rats at even 10-fold higher dosage.
在两组近交系小鼠（C57BL/6NCr、DBA/2NCr）以及5周龄时用N-亚硝基二乙胺（NDEA；小鼠90 mg/kg，大鼠75 mg/kg）启动的F344/NCr大鼠中，对1,4-双[2-(3,5-二氯吡啶氧基)]苯（TCPOBOP）在肝脏及其他器官中的促肿瘤和致癌作用进行了定量，并与苯巴比妥（PB）的作用进行了比较。两周后，动物每2周接受一次TCPOBOP处理（腹腔注射或灌胃），或在整个实验期间喂食含500 ppm PB的饲料作为阳性对照。小鼠接受TCPOBOP（3.0 mg/kg/剂量）处理30周，之后喂以对照饲料，而大鼠在整个78周的实验期间接受TCPOBOP处理方案（3.0或30 mg/kg/剂量）。TCPOBOP在两组小鼠中都是完全致癌物和极强的促癌剂，尤其是在DBA品系中，NDEA之后再用TCPOBOP（腹腔注射）导致所有动物在30周内死于多发性肝细胞肿瘤。单独使用TCPOBOP在60周内使DBA小鼠的肿瘤发生率达到100%。此外，在两组小鼠中，患有肝肿瘤的动物中有很大比例发生了肺转移。相比之下，即使给予F344大鼠的剂量是小鼠的10倍，TCPOBOP作为肝肿瘤促癌剂也无效。然而，有趣的是，在NDEA之后给予TCPOBOP，会使F344大鼠的鼻腔肿瘤显著增加。PB在雄性DBA小鼠和雄性F344大鼠中是有效的肝肿瘤促癌剂，但在C57小鼠中作为促癌剂相对无效。当比较促肿瘤活性和细胞色素P450 IIB1的诱导情况时，观察到这两个参数之间有很好的一致性。PB在大鼠和两组小鼠中都是P450 IIB1的有效诱导剂，并且在DBA小鼠和F344大鼠中都是强效的肝肿瘤促癌剂，而TCPOBOP在两组小鼠中都是强效诱导剂和肿瘤促癌剂，但即使剂量高出10倍，在F344大鼠中作为诱导剂或促癌剂的效果也微乎其微。
