Comparison of the aneugenic effect of vinorelbine and vincristine in cultured human lymphocytes.
Vinca alkaloids are used clinically against a variety of hematological and solid tumors. These compounds interact with tubulin subunits to prevent microtubule assembly, inducing abnormal chromosome segregation in dividing cells and causing aneuploidy. The vinca alkaloid vincristine sulfate (VCR) and the semisynthetic analog vinorelbine (VRB) were studied by analysis of micronuclei (MN) in cultured human lymphocytes using the cytokinesis block method. Furthermore, fluorescence in situ hybridization with a human alphoid satellite pancentromeric DNA probe was used to detect centromeres in isolated MN of VRB- or VCR-treated lymphocytes. At all the doses tested, both chemicals induced a significant increase in MN frequencies in binucleated (BN) cells (P < 0.001). The maximal effect was reached at a dose of 0.50 microgram/ml. At this dose, VRB produced an approximately 5-fold increase with respect to the control frequency of MN, while with VCR, this frequency increased 10-fold. Both drugs produced a slowing of the cell cycle, causing a decrease in the percentage of BN cells. This effect was lower with VRB. The percentages of centromere-positive MN were 89.79 and 87.60% in VRB- and VCR-treated cultures, respectively (control 27.03%). The high percentage of positive-signals in treated cultures (P < 0.001) indicates that the MN contained whole chromosomes. Our results confirm the aneugenic mode of action of these chemicals, VRB having less genetic effect.
González-Cid
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Departamento de Genética, Instituto de Investigaciones Hematológicas Mariano R. Castex, Academia Nacional de Medicina, Buenos Aires, Argentina. postmaster@anmra.sld.ar
Cuello
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MT
Larripa
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D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D002478:Cells, Cultured; D002503:Centromere / Q000187:drug effects; D005260:Female; D006131:Growth Inhibitors / Q000633:toxicity; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D008297:Male; D015162:Micronucleus Tests; D008875:Middle Aged; D008941:Spindle Apparatus / Q000187:drug effects*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000633:toxicity; D014750:Vincristine / Q000633:toxicity*; D000077235:Vinorelbine
D000972:Antineoplastic Agents, Phytogenic; D006131:Growth Inhibitors; D014750:Vincristine; D014747:Vinblastine; D000077235:Vinorelbine