Cytogenetic effects of cyclophosphamide on human lymphocytes in vivo and in vitro

Бочков, Н. П.; Filippova, T.V.; Kuzin, S. M.; Stukalov, S. V.

doi:10.1016/0027-5107(86)90118-1

Cited by 23 publications

(4 citation statements)

References 8 publications

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“…In humans, chromosome damage has been seen in peripheral blood lymphocytes (PBL) and/or bone marrow from patients and/or workers exposed to CP. Anderson et al [1995] state that the lowest effective dose was 35 mg/kg for human lymphocytes (as reported by [Bochkov et al, 1986] and 40 mg/kg for bone marrow cells recovered from five patients suffering from various malignancies (as reported by [Goetz et al, 1975]. Anderson et al [1995] also cite the findings of Hettner [1992] that indicated an increase in Hprt gene mutations ($4X higher than matched controls) in the PBL of 23 workers occupationally exposed to CP.…”

Section: Mutation/chromosomal Aberrationsmentioning

confidence: 61%

“…In humans, Bochkov et al [1986] reported chromosome aberrations and SCEs in lung cancer patients 2 hr postexposure to the initial treatment with single i.v. doses of 33-40 mg/kg CP, and Kahn et al [1998] found mutations in the p53 tumor suppressor gene in resected or biopsy tissue from the urinary bladders of patients receiving cumulative doses as low as 6 g. These data are in harmony with the results of Travis et al [1995] who studied the relationship between dose and effect within a cohort of 6,171 survivors of non-Hodgkin's lymphoma treated with CP.…”

Section: Mutagenic Eventsmentioning

confidence: 97%

“…For example, a time course study, conducted by Dearfield et al [1985] in the bone marrow of Fischer 344 rats dosed with 5, 10, or 20 mg/kg CP, showed a gradual time-dependent increase in SCEs starting as early as 30 min after exposure. In humans, Bochkov et al [1986] demonstrated chromosome aberrations and SCE induction in lung cancer patients within 2 hr of CP treatment. Similarly, regenerative proliferation occurs early [e.g., bladder damage within 1 day and repair and regeneration of the rat bladder within 4 days of treatment with a single i.p.…”

Section: Temporal Associationsmentioning

confidence: 99%

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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: Mutation/chromosomal Aberrationsmentioning

confidence: 61%

Section: Mutagenic Eventsmentioning

confidence: 97%

Section: Temporal Associationsmentioning

confidence: 99%

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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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“…It appears that alkylating agents such as melphalan are particularly likely to induce ANLL (Reimer er al., 1977;Einhorn, 1978;Nowell et al, 1981), but only a few studies on the chromosomal lesions they induce in vitro as well as in vivo have been published so far (Schinzel and Schmid, 1976;Meyne et al. 1979;Honeycombe, 1978;Reeves and Margoles, 1974;Kaina, 1977;KuEerova and Polivkova, 1976;Morad and El Zawahri, 1977;Lawler et al, 1982;Gebhart et al, 1980;Lambert et al, 1984;Bochkov et al, 1986).…”

mentioning

confidence: 99%

Chromosomal aberrations in lymphocytes of patients treated with melphalan

Mamuris

Gerbault‐Seureau

Prieur

et al. 1989

Intl Journal of Cancer

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Chromosome lesions detected in lymphocytes from 14 patients previously treated with melphalan, a bifunctional alkylating agent, have been analyzed on R‐banded preparations. In comparison to controls, there was no significant increase of chromatid‐type lesions, but chromosome‐type lesions were quite frequent, affecting 21.5% of metaphases, on the average. Reciprocal translocations represent 54%, unbalanced translocations 15%, deletions 19% and inversions 6% of all rearrangements. Most of these would not have been detected without the use of chromosome banding. The distributions of affected chromosomes and chromosome bands were not random. Almost all imbalances resulting from rearrangements lead to losses but not to gains. The distribution of the abnormal chromosomes has been compared to that observed in controls and in in vitro experiments, and to the characteristic pattern of malignant cells from patients affected by secondary acute leukemia (ANLL).

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Comparison of Hprt variant frequencies and chromosome aberration frequencies in lymphocytes from radiotherapy and chemotherapy patients: A Prospective Study

Ammenheuser

Whorton

et al. 1991

Environ and Mol Mutagen

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The autoradiographic 6-thioguanine-resistant mutant lymphocyte assay and a chromosome aberration assay were used to determine the time-course of appearance and persistence of elevated frequencies of hprt variants and dicentric chromosomes in patients receiving x-irradiation therapy. Twelve cancer patients, treated with 180-200 cGy/day, 5 days/wk, for 3-7 wk, were studied before treatment, at various weekly intervals during treatment, and after treatment. The hprt mutation assays were done with frozen/thawed lymphocytes isolated from aliquots of the same blood samples used for the chromosome aberration assays. The hprt variant frequencies (Vfs) of only 4 of the 7 patients assayed at 2 wk of treatment were elevated over pre-treatment Vfs, but during the 3rd and 4th weeks of treatment there were significant (P less than 0.01) 5- to 15-fold increases in all Vfs. By 6-32 wk after treatment Vfs had fallen to levels only slightly higher than the mean pre-treatment Vf. The frequencies of cells with dicentric chromosomes were significantly increased (P less than 0.01) after 1 wk of radiotherapy, continued to increase during therapy, and remained elevated after treatment. Five multiple sclerosis patients were also studied before and at 2 and 4 wk intervals after treatment with monthly i.v. doses of 750 mg/m2 of cyclophosphamide (CP). There were no significant elevations in chromosome aberrations at these post-treatment sample times. Previous assays for hprt mutants, done with aloquots of the same blood samples (Ammenheuser et al.: Mutat Res 204:509-520, 1988), had shown 8- to 20-fold increases in Vfs 2 wk after the 1st CP treatment. Our results demonstrate the complementary nature of these two human monitoring assays and emphasize the importance of careful selection of optimal sampling times.

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Cytogenetic effects of cyclophosphamide on human lymphocytes in vivo and in vitro

Cited by 23 publications

References 8 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

Chromosomal aberrations in lymphocytes of patients treated with melphalan

Comparison of Hprt variant frequencies and chromosome aberration frequencies in lymphocytes from radiotherapy and chemotherapy patients: A Prospective Study

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