Early Effects of Cyclophosphamide on Mouse Bladder Epithelium

Campobasso, O; Berrino, Franco

doi:10.1159/000162399

Cited by 9 publications

(5 citation statements)

References 9 publications

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“…By the end of the study (25 days), Koss stated that ''... the epithelium showed a markedly atypical papillary hyperplasia.'' Similar evidence of cytotoxicity leading to a proliferative response in mouse bladder was reported by Campobasso and Berrino [1972] within 3 days of a single i.p. administration of 10 mg/kg CP to male and female Swiss mice.…”

Section: Regenerative Proliferationsupporting

confidence: 81%

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An evaluation of the mode of action framework for mutagenic carcinogens case study: Cyclophosphamide

McCarroll

Keshava

Cimino

et al. 2008

Environ and Mol Mutagen

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In response to the 2005 revised US Environmental Protection Agency (EPA) Cancer Guidelines, a Risk Assessment Forum's Technical Panel has devised a strategy in which genetic toxicology data combined with other information are assessed to determine whether a carcinogen operates through a mutagenic mode of action (MOA). This information is necessary for EPA to decide whether age-dependent adjustment factors (ADAFs) should be applied to the cancer risk assessment. A decision tree has been developed as a part of this approach and outlines the critical steps for analyzing a compound for carcinogenicity through a mutagenic MOA (e.g., data analysis, determination of mutagenicity in animals and in humans). Agents, showing mutagenicity in animals and humans, proceed through the Agency's framework analysis for MOAs. Cyclophosphamide (CP), an antineoplastic agent, which is carcinogenic in animals and humans and mutagenic in vitro and in vivo, was selected as a case study to illustrate how the framework analysis would be applied to prove that a carcinogen operates through a mutagenic MOA. Consistent positive results have been seen for mutagenic activity in numerous in vitro assays, in animals (mice, rats, and hamsters) and in humans. Accordingly, CP was processed through the framework analysis and key steps leading to tumor formation were identified as follows: metabolism of the parent compound to alkylating metabolites, DNA damage followed by induction of multiple adverse genetic events, cell proliferation, and bladder tumors. Genetic changes in rats (sister chromatid exchanges at 0.62 mg/kg) can commence within 30 min and in cancer patients, chromosome aberrations at 35 mg/kg are seen by 1 hr, well within the timeframe and tumorigenic dose range for early events. Supporting evidence is also found for cell proliferation, indicating that mutagenicity, associated with cytotoxicity, leads to a proliferative response, which occurs early (48 hr) in the process of tumor induction. Overall, the weight of evidence evaluation supports CP acting through a mutagenic MOA. In addition, no data were found that an alternative MOA might be operative. Therefore, the cancer guidelines recommend a linear extrapolation for the risk assessment. Additionally, data exist showing that CP induces mutagenicity in fetal blood and in the peripheral blood of pediatric patients; thus, the ADAFs would be applied.

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Section: Regenerative Proliferationsupporting

confidence: 81%

“…IARC cites the data from several studies [Phillips et al, 1961;Koss, 1967;Campobasso and Berrino, 1972] indicating that administration of a single i.p. dose of CP caused marked necrosis of the urinary bladder in rats and dogs.…”

Section: Regenerative Proliferationmentioning

confidence: 99%

An evaluation of the mode of action framework for mutagenic carcinogens case study: Cyclophosphamide

McCarroll

Keshava

Cimino

et al. 2008

Environ and Mol Mutagen

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“…Squamous metaplasias were found in a significant number of bladder tumors in 2-AAF-treated mice (80). Furthermore, the normal progression from diploid basal, through tetraploid intermediate to octaploid or hyperploid superficial cells which are characteristic of the normal urothelium (15), is disrupted by cy-clophosphamide, and temporarily there is aneuploidy with many hyperpolyploid nuclei (81). Cyclophosphamide causes first cytotoxic damage and strips the urothelium from the basal lamina, but the subsequent hyperplasias are both undifferentiated and dysplastic.…”

Section: Induction Of Dark Basal Cells Dark Basal Cells Comparable Tmentioning

confidence: 99%

Effect of Promoters on Incidence of Bladder Cancer in Experimental Animal Models

Hicks¹

1983

Environmental Health Perspectives

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“…Cyclophosphamide causes first cytotoxic damage and strips the urothelium from the basal lamina, but the subsequent hyperplasias are both undifferentiated and dysplastic. Furthermore, the normal progression from diploid basal, through tetraploid intermediate to octaploid or hyperploid superficial cells which are characteristic of the normal urothelium (15), is disrupted by cy-clophosphamide, and temporarily there is aneuploidy with many hyperpolyploid nuclei (81).…”

Section: In the Rat Urinary Bladdermentioning

confidence: 99%

Effect of promoters on incidence of bladder cancer in experimental animal models.

Hicks¹

1983

Environ Health Perspect

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Multistage models of carcinogenesis proposed to account for the observed patterns of tumor development in the skin, liver, lung, bladder and other organs involve initiation of neoplastic change in a few cells by a threshold dose of carcinogen followed by conversion of these latent tumor cells into an autonomous cancer by further doses of the same and/or other carcinogens, and/or noncarcinogenic promoting agents. In the rat urinary bladder, neoplastic change can be initiated by a few weeks treatment with low doses of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) or N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or by a single, low dose, intravesicular instillation of N-methyl-N-nitrosourea (MNU). Very few animals treated thus will develop bladder cancer unless exposed subsequently to some further regime which will promote tumor growth from the initiated cells. Many different factors will stimulate tumor growth in the initiated rat bladder, including further low doses of complete bladder carcinogens, dietary factors such as metabolites of tryptophan or deficiency of vitamin A, the food additives saccharin and cyclamate and some alkylating agents such as cyclophosphamide and methylmethane sulfonate. New and published evidence is reviewed which supports the belief that these and other factors are promoters or later stage carcinogens in the bladder. The difficulties of defining a promoter and of identifying markers of promotion, i.e., of distinguishing the second from the later stages of carcinogenesis in the urinary bladder, are discussed with reference to the action of promoters in the mouse skin initiation/promotion model. However, in terms of their effect on an initiated population on the risk of developing cancer, it is suggested that such a distinction is largely irrelevant. Since both second and later stage carcinogens accelerate tumor development in an initiated urothelium, they both have the potential to lower the age at which bladder cancer becomes symptomatic. They are thus as important as are initiating carcinogens in determining the patterns of age-related neoplastic disease in any population.ImagesFIGURE 1.FIGURE 2.FIGURE 3.FIGURE 4.FIGURE 5.FIGURE 6.

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Early Effects of Cyclophosphamide on Mouse Bladder Epithelium

Cited by 9 publications

References 9 publications

An evaluation of the mode of action framework for mutagenic carcinogens case study: Cyclophosphamide

An evaluation of the mode of action framework for mutagenic carcinogens case study: Cyclophosphamide

Effect of Promoters on Incidence of Bladder Cancer in Experimental Animal Models

Effect of promoters on incidence of bladder cancer in experimental animal models.

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