Phenolphthalein induces thymic lymphomas accompanied by loss of the p53 wild type allele in heterozygous p53-deficient (±) mice
Phenolphthalein induces thymic lymphomas accompanied by loss of the p53 wild type allele in heterozygous p53-deficient (±) mice
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DOI：
10.1177/019262339702500601
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发表时间：
1997-11-01
影响因子：
1.5
通讯作者：
French, JE
中科院分区：
文献类型：
--
作者：
Dunnick, JK;Hardisty, JE;French, JE
流行病学研究表明，许多人类癌症受到环境因素的影响。转基因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相互作用的机会。以杂合型P53基因缺失(+/-)小鼠为模型，研究了酚酞对肿瘤诱导和P53基因突变的影响。早期的研究表明，酚酞在服药2年后对Fisher 344大鼠和B6C3F(1)小鼠产生致癌作用(Dunnick和Hailey，癌症研究56：4922-4926,1996)。P53(+/-)小鼠在饲料中以200、375、750、3,000或12,000 ppm的浓度(约43、84、174、689或2,375 mg/kg体重/天或129、252、522、2,867或7,128 mg/m(2)体表面积/天)接受最多6个月的酚酞注射。在B6C3F(1)小鼠中积累P53蛋白的靶器官癌部位(即胸腺淋巴瘤)也是P53(+/-)小鼠的癌靶部位。在p53(+/-)小鼠中，对照组和剂量组出现与治疗相关的不典型增生和胸腺起源的恶性淋巴瘤，联合发生率分别为0、5、5、25、100和95%。对21例胸腺淋巴瘤进行了p53基因突变检测，均表现为p53野生型等位基因缺失。在B6C3F(1)小鼠中，化学诱导的卵巢肿瘤没有发现P53蛋白积聚的证据，在P53(+/-)小鼠中也没有发生。P53基因缺陷(+/-)小鼠模型对酚酞治疗的反应是胸腺在仅仅4个月的剂量后出现致癌反应。在传统的B6C3F(1)小鼠生物试验中，这种致癌反应花了两年时间才形成。P53基因缺陷(+/-)小鼠是识别短期(
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 B6C3F(1) 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/m(2) body surface area/day) for up to 6 mo. A target organ cancer site that accumulated p53 protein in the B6C3F(1) 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 B6C3F(1) 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 B6C3F(1) mouse bioassay. The p53-deficient (+/-) mouse is an important model for identifying a carcinogenic response after short-term (