Phenolphthalein Induces Thymic Lymphomas Accompanied by Loss of the p53 Wild Type Allele in Heterozygous p53-Deficient (±) Mice

Dunnick, June K.; Hardisty, Jerry F.; Herbert, Ron; Seely, John C.; Furedi-Machacek, E M; Foley, Julie F.; Lacks, Gregory D.; Stasiewicz, Stanley; French, John E.

doi:10.1177/019262339702500601

Cited by 74 publications

(47 citation statements)

References 34 publications

(27 reference statements)

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“…However, ovarian cancer was not seen in this study (Dunnick et al, 1997), and there was no evidence of p53 protein accumulation in the ovarian tumours in the previous study using B6C3F 1 mice (Dunnick and Hailey 1996;National Toxicology Program, 1996). Phenolphthalein has oestrogenic properties, and another potential mechanism through which phenolphthalein could effect ovarian cancer is through its interaction with the estrogen-receptor (Ravdin et al 1987).…”

Section: Discussioncontrasting

confidence: 69%

“…Phenolphthalein was shown to induce thymic lymphomas in heterozygous p53-deficient mice after only 4 months of exposure, and loss of the p53 wild-type allele was demonstrated in all of the lymphomas (Dunnick et al, 1997). However, ovarian cancer was not seen in this study (Dunnick et al, 1997), and there was no evidence of p53 protein accumulation in the ovarian tumours in the previous study using B6C3F 1 mice (Dunnick and Hailey 1996;National Toxicology Program, 1996).…”

Section: Discussionmentioning

confidence: 48%

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Risk of ovarian cancer in relation to use of phenolphthalein-containing laxatives

et al. 2000

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We examined ovarian cancer risk in relation to use of phenolphthalein-containing laxatives in 410 epithelial ovarian cancer cases and 713 controls. Compared to women who never used a laxative, ever use of a phenolphthalein-containing laxative was not associated with an increased risk of ovarian cancer (odds ratio, OR, 1.1, 95% confidence interval, CI, 0.9–1.4). Risk was slightly, but not significantly, higher with more frequent use (OR 1.2 for 75 or more days of use). When women who used non-phenolphthalein containing laxatives was used as the reference group, the associations were slightly, but not significantly larger (OR 1.4 for any use of phenolphthalein-containing laxatives and OR 1.5 for 75 or more days of use) © 2000 Cancer Research Campaign

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Section: Discussioncontrasting

confidence: 69%

Section: Discussionmentioning

confidence: 48%

Risk of ovarian cancer in relation to use of phenolphthalein-containing laxatives

et al. 2000

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“…In addition, PhP has been reported to be positive in chromosomal aberration test of cultured Chinese hamster ovary cells and micronucleus test of peripheral blood samples from mice [14]. Furthermore, malignant lymphomas of thymic origin were also induced in p53 (+/-) TSG mice by the treatment with PhP for 6 months [7]. However, PhP rarely induced hepatocellular proliferative lesions in p53 (+/-) and p53 (+/+) CBA mice in our study.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of Liver Proliferative Lesions in Heterozygous p53 Deficient CBA Mice to Various Carcinogens.

Uehara

Kashida

Watanabe

et al. 2002

The Journal of Veterinary Medical Science

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ABSTRACT. To investigate the liver tumorigenic sensitivity to various carcinogens in heterozygous p53 deficient [p53 (+/-)] CBA mice and their wild-type littermates [p53 (+/+) mice], 71 p53 (+/-) and 74 p53 (+/+) CBA mice (male, 6-12 weeks of age) were given diet containing 4,000 or 0 ppm flumequine (FL) for 26 weeks or a single intraperitoneal injection of 5 mg/kg body weights dimethylnitros amine (DMN) at start of the study in Exp. 1, diet containing 6,000 or 0 ppm di(2-ethylhexyl)-phthalate (DEHP) for 26 weeks in Exp. 2, or diet containing 12,000, 6,000 or 0 ppm phenolphthalein (PhP) for 26 weeks in Exp. 3. All surviving animals of these groups were killed after completion of treatment of the test substances for 26 weeks. In the FL groups, the incidences of hepatocellular altered f oci in p53 (+/-) mice, the multiplicities of those in p53 (+/-) and p53 (+/+) mice were significantly increased as compared to the corresponding control groups. The incidences and multiplicities of altered foci in the DMN groups were higher than those in the corresponding control groups in p53 (+/-) and p53 (+/+) mice, but no significant differences were indicated between the groups. There were no significant differences in the incidences, multiplicities and proliferating cell nuclear antigen labeling indices of altered foci in the FL or DMN groups between p53 (+/-) and p53 (+/+) mice. There were no significant differences in the incidences and multiplicities of altered foci between the DEHP or PhP and control groups. The present results suggest that p53 gene knocked out heterozygously does not enhance the chemical hepatocarcinogenesis in CBA mice. KEY WORDS: dimethylnitrosamine, di(2-ethylhexyl)-phthalate, flumequine, phenolphthalein, p53 (+/-) CBA mouse.

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“…PhP has carcinogenic activity, causing pheochromocytomas of the adrenal medulla and renal tubular adenomas/carcinomas in F344 rats as well as histiocytic sarcomas, malignant lymphomas and sex-cord stromal tumors of the ovary in B6C3F1 mice [2]. In addition, malignant thymic lymphomas were also induced in heterozygous p53-deficient female mice given PhP for 6 months [3]. From these studies, it has been recognized that the tumor target organs of PhP were the hematopoietic system, ovary, kidney, and adrenal gland [2].…”

Section: Discussionmentioning

confidence: 99%

“…It has carcinogenic activity to rats and mice in 2-year carcinogenicity studies, causing neoplasms of the kidney and adrenal medulla in rats and hematopoietic and ovary tumors in mice [2]. In addition, malignant lymphomas of thymic origin were also induced in heterozygous p53 deficient TSG mice [3]. However, it is unknown whether the lung is the tumor target organ of PhP.…”

mentioning

confidence: 99%

Tumor Promoting Effect of Phenolphthalein on Development of Lung Tumors Induced by N-ethyl-N-nitrosourea in Transgenic Mice Carrying Human Prototype c-Ha-ras Gene.

Imaoka

Kashida

Watanabe

et al. 2002

The Journal of Veterinary Medical Science

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ABSTRACT. In order to examine tumor modifying effects of phenolphthalein (PhP), female transgenic mice carrying human prototype cHa-ras gene (rasH2 mice) were given a single intraperitoneal injection of 60 mg/kg body weight of N-ethyl-N-nitrosourea (ENU), followed by the diet containing 12,000 ppm PhP for 26-week. Histopathologically, alveolar hyperplasias, adenomas and adenocarcinomas were observed in the ENU + PhP group, but only hyperplasias and adenomas were observed in the ENU alone group. The incidence and multiplicity of adenocarcinomas in the ENU + PhP group was significantly increased as compared to that in the ENU alone group. The combined multiplicity of adenomas and adenocarcinomas in this group was also significantly higher than that of the ENU alone group. In addition, the ratio of area of adenomas in the ENU + PhP group was significantly higher than that in the ENU alone group. The result of our study suggests that PhP has a clear tumor promoting effect in the lung of rasH2 mice. KEY WORDS: lung tumor, phenolphthalein, rasH2 mouse, tumor promotion.

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Phenolphthalein Induces Thymic Lymphomas Accompanied by Loss of the p53 Wild Type Allele in Heterozygous p53-Deficient (±) Mice

Cited by 74 publications

References 34 publications

Risk of ovarian cancer in relation to use of phenolphthalein-containing laxatives

Risk of ovarian cancer in relation to use of phenolphthalein-containing laxatives

Susceptibility of Liver Proliferative Lesions in Heterozygous p53 Deficient CBA Mice to Various Carcinogens.

Tumor Promoting Effect of Phenolphthalein on Development of Lung Tumors Induced by N-ethyl-N-nitrosourea in Transgenic Mice Carrying Human Prototype c-Ha-ras Gene.

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