Involvement of gene-specific DNA damage and apoptosis in the differential toxicity of mitomycin C analogs towards B-lineage versus T-lineage lymphoma cells.
Avian and mammalian B- and T-lineage lymphocytes display differential sensitivity to a variety of genotoxic agents. Specifically, T-lineage cells show a high degree of resistance to the toxic effects of exposure to chemotherapeutic drugs, whereas B-lineage cells show a high degree of sensitivity. We used a model system consisting of virally transformed B- and T-lymphoma cell lines to further define the cellular and molecular mechanisms responsible for the differential toxicity of two chemotherapeutic drugs that induce DNA-interstrand cross-links to different degrees, mitomycin C (MMC) and its aminodisulfide analog, BMY 25067. Quantification of the number of cross-links introduced in the transcriptionally active ribosomal RNA gene cluster revealed that similar levels of DNA damage were induced in B- and T-lymphoma cell lines. However, B-lymphoma cells were highly sensitive to induction of apoptosis and inhibition of growth compared with the more resistant T-lymphoma cells for both compounds. BMY 25067 induced approximately 2-fold more cross-links in rDNA than did MMC, along with a concurrent enhanced induction of apoptosis in both B- and T-lymphoma cell lines. An analysis of the persistence of DNA lesions over multiple cell cycles revealed that neither B- nor T-lymphoma cells repaired DNA cross-links to a significant extent. These data suggest that differences in the extent or persistence of DNA-interstrand cross-links are not responsible for the differential toxicity of MMC and its analog towards B- versus T-lineage cells. Rather, differential drug toxicity involves early and extensive entry into apoptosis in B-lymphoma cells contrasted to the delayed and minimal apoptotic induction in T-lymphoma cells.
Muscarella
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Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Bloom
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D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002645:Chickens; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000473:pathology; D016685:Mitomycin / Q000494:pharmacology*; D008937:Mitomycins; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D008937:Mitomycins; D016685:Mitomycin; D004247:DNA; C055172:N-7-(2-(nitrophenyldithio)ethyl)mitomycin C