Dunnick J K, Hardisty J F, Herbert R A, Seely J C, Furedi-Machacek E M, Foley J F, Lacks G D, Stasiewicz S, French J E
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Toxicol Pathol. 1997 Nov-Dec;25(6):533-40. doi: 10.1177/019262339702500601.
Epidemiology studies have indicated that many human cancers are influenced by environmental factors. Genetically altered mouse model systems offer us the opportunity to study the interaction of chemicals with genetic predisposition to cancer. Using the heterozygous p53-deficient (+/-) mouse, an animal model carrying one wild type p53 gene and one p53 null allele, we studied the effects of phenolphthalein on tumor induction and p53 gene alterations. Earlier studies showed that phenolphthalein caused carcinogenic effects in Fisher 344 rats and B6C3F1 mice after a 2-yr dosing period (Dunnick and Hailey, Cancer Res. 56: 4922-4926, 1996). The p53 (+/-) mice received phenolphthalein in the feed at concentrations of 200, 375, 750, 3,000, or 12,000 ppm (approximately 43, 84, 174, 689, or 2,375 mg/kg body weight/day or 129, 252, 522, 2,867, or 7,128 mg/m2 body surface area/day) for up to 6 mo. A target organ cancer site that accumulated p53 protein in the B6C3F1 mouse (i.e., thymic lymphoma) was also a target site for cancer in the p53 (+/-) mouse. In the p53 (+/-) mouse, treatment-related atypical hyperplasia and malignant lymphoma of thymic origin were seen in the control and dosed groups at a combined incidence of 0, 5, 5, 25, 100, and 95%, respectively. Twenty-one of the thymic lymphomas were examined for p53 gene changes, and all showed loss of the p53 wild type allele. Chemical-induced ovarian tumors in the B6C3F1 mouse showed no evidence for p53 protein accumulation and did not occur in the p53 (+/-) mouse. The p53-deficient (+/-) mouse model responded to phenolphthalein treatment with a carcinogenic response in the thymus after only 4 mo of dosing. This carcinogenic response took 2 yr to develop in the conventional B6C3F1 mouse bioassay. The p53-deficient (+/-) mouse is an important model for identifying a carcinogenic response after short-term (< 6 mo) exposures. Our studies show that exposure to phenolphthalein combined with a genetic predisposition to cancer can potentiate the carcinogenic process and cause p53 gene alterations, a gene alteration found in many human cancers.
流行病学研究表明，许多人类癌症受到环境因素的影响。基因改造的小鼠模型系统为我们提供了研究化学物质与癌症遗传易感性之间相互作用的机会。我们使用杂合型p53基因缺陷（+/-）小鼠，这是一种携带一个野生型p53基因和一个p53无效等位基因的动物模型，研究了酚酞对肿瘤诱导和p53基因改变的影响。早期研究表明，在给予2年剂量后，酚酞在费希尔344大鼠和B6C3F1小鼠中具有致癌作用（邓尼克和黑利，《癌症研究》56:4922 - 4926，1996年）。p53（+/-）小鼠在饲料中接受浓度为200、375、750、3000或12000 ppm（分别约为43、84、174、689或2375毫克/千克体重/天或129、252、522、2867或7128毫克/平方米体表面积/天）的酚酞，持续长达6个月。在B6C3F1小鼠中积累p53蛋白的靶器官癌症部位（即胸腺淋巴瘤）也是p53（+/-）小鼠中的癌症靶部位。在p53（+/-）小鼠中，对照组和给药组中均出现了与治疗相关的胸腺起源的非典型增生和恶性淋巴瘤，合并发生率分别为0、5、5、25、100和95%。对21例胸腺淋巴瘤进行了p53基因变化检测，所有结果均显示p53野生型等位基因缺失。B6C3F1小鼠中化学诱导的卵巢肿瘤未显示p53蛋白积累的证据，且在p53（+/-）小鼠中未发生。p53基因缺陷（+/-）小鼠模型在仅给药4个月后，胸腺就对酚酞治疗产生了致癌反应。在传统的B6C3F1小鼠生物测定中，这种致癌反应需要2年时间才会出现。p53基因缺陷（+/-）小鼠是用于识别短期（<6个月）暴露后致癌反应的重要模型。我们的研究表明，接触酚酞并伴有癌症遗传易感性会增强致癌过程，并导致p53基因改变，这种基因改变在许多人类癌症中都有发现。
