Organ-specific genotoxicity of the potent rodent colon carcinogen 1,2-dimethylhydrazine and three hydrazine derivatives: difference between intraperitoneal and oral administration

Sasaki, Yu; Saga, Ayako; Akasaka, Makiko; Ishibashi, Satoko; Yoshida, Kumiko; Su, Ying Quan; Matsusaka, Naonori; Tsuda, Shuji

doi:10.1016/s1383-5718(98)00002-3

Cited by 30 publications

(19 citation statements)

References 22 publications

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“…As also is revealed in a number of earlier published studies (almost all conducted in mice) (Wild, ; Inouye et al, ; Romagna and Schneider, ; Vanparys et al, ; Suzuki et al, ; Phonethepswath et al, ), we found a robust induction of micronuclei in both peripheral blood and bone marrow at all analyzed timepoints or upon terminal sacrifice using both treatment regimens. Similarly, the alkaline Comet assay detected significant %tail DNA increases in the liver, kidney, lung, and peripheral blood of PCZ‐treated rats, which is consistent with previous positive findings for these tissue types in PCZ‐treated rodents (Sasaki et al, ; ; Sekihashi et al, ). The positive Comet responses in these tissues/systems are not surprising because these sites are also targets for other relevant genotoxic or carcinogenic effects.…”

Section: Discussion and Summarysupporting

confidence: 89%

Assessment of the Pig‐a, micronucleus, and comet assay endpoints in rats treated by acute or repeated dosing protocols with procarbazine hydrochloride and ethyl carbamate

Gaofeng

Wen

Zhihui

et al. 2018

Environ and Mol Mutagen

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The utility and sensitivity of the newly developed flow cytometric Pig‐a gene mutation assay have become a great concern recently. In this study, we have examined the feasibility of integrating the Pig‐a assay as well as micronucleus and Comet endpoints into acute and subchronic general toxicology studies. Male Sprague–Dawley rats were treated for 3 or 28 consecutive days by oral gavage with procarbazine hydrochloride (PCZ) or ethyl carbamate (EC) up to the maximum tolerated dose. The induction of CD59‐negative reticulocytes and erythrocytes, micronucleated reticulocytes in peripheral blood, micronucleated polychromatic erythrocytes in bone marrow, and Comet responses in peripheral blood, liver, kidney, and lung were evaluated at one, two, or more timepoints. Both PCZ and EC produced positive responses at most analyzed timepoints in all tissue types, both with the 3‐day and 28‐day treatment regimens. Furthermore, comparison of the magnitude of the genotoxicity responses indicated that the micronucleus and Comet endpoints generally produced greater responses with the higher dose, short‐term treatments in the 3‐day study, while the Pig‐a assay responded better to the cumulative effects of the lower dose, but repeated subchronic dosing in the 28‐day study. Collectively, these results indicate that integration of several in vivo genotoxicity endpoints into a single routine toxicology study is feasible and that the Pig‐a assay may be particularly suitable for integration into subchronic dose studies based on its ability to accumulate the mutations that result from repeated treatments. This characteristic may be especially important for assaying lower doses of relatively weak genotoxicants. Environ. Mol. Mutagen. 60:56–71, 2019. © 2018 Wiley Periodicals, Inc.

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Section: Discussion and Summarysupporting

confidence: 89%

Assessment of the Pig‐a, micronucleus, and comet assay endpoints in rats treated by acute or repeated dosing protocols with procarbazine hydrochloride and ethyl carbamate

Gaofeng

Wen

Zhihui

et al. 2018

Environ and Mol Mutagen

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“…Our finding is the first observation of increased stomach cancer risk in humans. In mice, intravenously administered procarbazine did not increase the risk of stomach cancer, whereas oral procarbazine did (37), likely related to direct exposure of the stomach mucosa to procarbazine. Prolonged exposure could also play a role, because the stomach is a storage organ and procarbazine was also used as single-agent maintenance treatment during 1 to 2 years in the 1970s.…”

Section: Discussionmentioning

confidence: 89%

Roles of Radiation Dose and Chemotherapy in the Etiology of Stomach Cancer as a Second Malignancy

Belt-Dusebout

Aleman

Besseling

et al. 2009

International Journal of Radiation Oncology*Biology*Physics

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“…PCH appears to be a particularly effective in vivo clastogen inducing both micronuclei in bone marrow (Romagna and Schneider 1990) and DNA breaks as detected by the alkaline elution (Holme et al 1989) and comet (Sasaki et al 1998) assays in multiple tissues including stomach and liver. Furthermore, significant increases in median percent tail DNA were recently reported in bone marrow, liver, kidney, and lungs of rats, 1 day after a 28-day exposure to 30 or 60 mg PCH/kg/day (Chen et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Integrated In Vivo Genotoxicity Assessment of Procarbazine Hydrochloride Demonstrates Induction of Pig‐a and LacZ Mutations, and Micronuclei, in MutaMouse Hematopoietic Cells

Maurice

Dertinger

Yauk

et al. 2019

Environ and Mol Mutagen

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Procarbazine hydrochloride (PCH) is a DNA‐reactive hematopoietic carcinogen with potent and well‐characterized clastogenic activity. However, there is a paucity of in vivo mutagenesis data for PCH, and in vitro assays often fail to detect the genotoxic effects of PCH due to the complexity of its metabolic activation. We comprehensively evaluated the in vivo genotoxicity of PCH on hematopoietic cells of male MutaMouse transgenic rodents using a study design that facilitated assessments of micronuclei and Pig‐a mutation in circulating erythrocytes, and lacZ mutant frequencies in bone marrow. Mice were orally exposed to PCH (0, 6.25, 12.5, and 25 mg/kg/day) for 28 consecutive days. Blood samples collected 2 days after cessation of treatment exhibited significant dose‐related induction of micronuclei in both immature and mature erythrocytes. Bone marrow and blood collected 3 and 70 days after cessation of treatment also showed significantly elevated mutant frequencies in both the lacZ and Pig‐a assays even at the lowest dose tested. PCH‐induced lacZ and Pig‐a (immature and mature erythrocytes) mutant frequencies were highly correlated, with R 2 values ≥0.956, with the exception of lacZ vs. Pig ‐ a mutants in mature erythrocytes at the 70‐day time point (R 2 = 0.902). These results show that PCH is genotoxic in vivo and demonstrate that the complex metabolism and resulting genotoxicity of PCH is best evaluated in intact animal models. Our results further support the concept that multiple biomarkers of genotoxicity, especially hematopoietic cell genotoxicity, can be readily combined into one study provided that adequate attention is given to manifestation times. Environ. Mol. Mutagen. 60:505–512, 2019. © 2018 Her Majesty the Queen in Right of Canada

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Organ-specific genotoxicity of the potent rodent colon carcinogen 1,2-dimethylhydrazine and three hydrazine derivatives: difference between intraperitoneal and oral administration

Cited by 30 publications

References 22 publications

Assessment of the Pig‐a, micronucleus, and comet assay endpoints in rats treated by acute or repeated dosing protocols with procarbazine hydrochloride and ethyl carbamate

Assessment of the Pig‐a, micronucleus, and comet assay endpoints in rats treated by acute or repeated dosing protocols with procarbazine hydrochloride and ethyl carbamate

Roles of Radiation Dose and Chemotherapy in the Etiology of Stomach Cancer as a Second Malignancy

Integrated In Vivo Genotoxicity Assessment of Procarbazine Hydrochloride Demonstrates Induction of Pig‐a and LacZ Mutations, and Micronuclei, in MutaMouse Hematopoietic Cells

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