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 exposur e to chemotherapeutic drugs, whereas B-lineage cells show a high degre e of sensitivity. We used a model system consisting of virally transfo rmed B- and T-lymphoma cell lines to further define the cellular and m olecular mechanisms responsible for the differential toxicity of two c hemotherapeutic drugs that induce DNA-interstrand cross-links to diffe rent degrees, mitomycin C (MMC) and its aminodisulfide analog, BMY 250 67. Quantification of the number of cross-links introduced in the tran scriptionally active ribosomal RNA gene cluster revealed that similar levels of DNA damage were induced in B- and T-lymphoma cell lines. How ever, 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 ind uction of apoptosis in both B- and T-lymphoma cell lines. An analysis of the persistence of DNA lesions over multiple cell cycles revealed t hat neither B- nor T-lymphoma cells repaired DNA cross-links to a sign ificant extent. These data suggest that differences in the extent or p ersistence of DNA-interstrand cross-links are not responsible for the differential toxicity of MMC and its analog towards B- versus T-lineag e cells. Rather, differential drug toxicity involves early and extensi ve entry into apoptosis in B-lymphoma cells contrasted to the delayed and minimal apoptotic induction in T-lymphoma cells. (C) 1997 Elsevier Science Inc.