Induction of chromosomal aberrations by dacarbazine in somatic and germinal cells of mice.
Dacarbazine (DTIC) is a chemotherapeutic agent that has been successfully applied to treat various types of cancer such as Hodgkin's disease, malignant melanomas, soft tissue sarcomas and advanced neuroblastomas. Many of the patients are of reproductive age and express concern over the genetic risk of the treatment they receive. Therefore, DTIC was tested for its clastogenic effects in somatic and germinal cells of mice. In the bone marrow micronucleus assay DTIC induced micronuclei that increased linearly in the dose range 0-125 mg/kg. In a dominant lethal study DTIC gave a positive response at the dose of 500 mg/kg when conceptions occurred 5-16 days after treatment, corresponding to treated spermatids and early spermatozoa. The induction of heritable translocations was tested in that sensitive period. The observed translocation rate among the F(1) progeny of male mice treated with 500 mg/kg DTIC was 2.13% (P < 00.1 against the historical control of 0.05%). Assuming linearity of the dose-response effect, the point estimate was used to calculate a doubling dose for the induction of heritable translocations of 12 mg/kg. Alternatively, an induced translocation rate of 41.6x10(-6) per unit dose was calculated. Both figures indicate that an increased genetic risk may exist for male patients after chemotherapy with DTIC under the assumption that germ cells of mice and humans are equally sensitive to the clastogenic effects of DTIC. However, the genetic risk is restricted to conceptions within a period of 40 days after the end of chemotherapy, since the sensitive stages of spermatogenesis are spermatids and early spermatozoa.
Institut für Experimentelle Genetik, GSF-Forschungszentrum für Umwelt und Gesundheit, Ingolstaedter Landstrasse 1, D-85764 Neuherberg, Germany. adler@gsf.de
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D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D002869:Chromosome Aberrations / Q000187:drug effects*; D003606:Dacarbazine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005298:Fertility / Q000187:drug effects; D005799:Genes, Dominant; D005804:Genes, Lethal; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007274:Injections, Intraperitoneal; D007621:Karyotyping; D008297:Male; D008540:Meiosis / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D015162:Micronucleus Tests; D008940:Mitotic Index; D013094:Spermatozoa / Q000187:drug effects*; D014178:Translocation, Genetic / Q000187:drug effects*
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine