PHENOLPHTHALEIN INDUCES THYMIC LYMPHOMAS ACCOMPANIED BY LOSS OF THE P53 WILD-TYPE ALLELE IN HETEROZYGOUS P53-DEFICIENT (+ -)MICE/

Epidemiology studies have indicated that many human cancers are influe nced by environmental factors. Genetically altered mouse model systems offer us the opportunity to study the interaction of chemicals with g enetic predisposition to cancer. Using the heterozygous p53-deficient (+/-) mouse, an animal model carrying one wild type p53 gene and one p 53 null allele, we studied the effects of phenolphthalein on tumor ind uction and p53 gene alterations. Earlier studies showed that phenolpht halein caused carcinogenic effects in Fisher 344 rats and B6C3F(1) mic e 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 (approximatel y 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 hyperpl asia 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 p5 3 gene changes, and all showed loss of the p53 wild type allele. Chemi cal-induced ovarian tumors in the B6C3F(1) mouse showed no evidence fo r p53 protein accumulation and did not occur in the p53 (+/-) mouse. T he p53-deficient (+/-) mouse model responded to phenolphthalein treatm ent with a carcinogenic response in the thymus after only 4 mo of dosi ng. This carcinogenic response took 2 yr to develop in the conventiona l B6C3F(1) mouse bioassay. The p53-deficient (+/-) mouse is an importa nt model for identifying a carcinogenic response after short-term (<6 mo) exposures. Our studies show that exposure to phenolphthalein combi ned with a genetic predisposition to cancer can potentiate the carcino genic process and cause p53 gene alterations, a gene alteration found in many human cancers.