Muscarella D E, Bloom S E
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Biochem Pharmacol. 1997 Mar 21;53(6):811-22. doi: 10.1016/s0006-2952(97)00009-9.
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.
鸟类和哺乳动物的B淋巴细胞系和T淋巴细胞系对多种基因毒性剂表现出不同的敏感性。具体而言，T淋巴细胞系细胞对接触化疗药物的毒性作用具有高度抗性，而B淋巴细胞系细胞则表现出高度敏感性。我们使用了一个由病毒转化的B淋巴瘤和T淋巴瘤细胞系组成的模型系统，以进一步确定导致两种诱导不同程度DNA链间交联的化疗药物（丝裂霉素C（MMC）及其氨基二硫化物类似物BMY 25067）产生不同毒性的细胞和分子机制。对转录活性核糖体RNA基因簇中引入的交联数量进行定量分析表明，B淋巴瘤和T淋巴瘤细胞系中诱导的DNA损伤水平相似。然而，与对两种化合物更具抗性的T淋巴瘤细胞相比，B淋巴瘤细胞对凋亡诱导和生长抑制高度敏感。BMY 25067在rDNA中诱导的交联比MMC多约2倍，同时在B淋巴瘤和T淋巴瘤细胞系中凋亡诱导均增强。对多个细胞周期中DNA损伤持续性的分析表明，B淋巴瘤细胞和T淋巴瘤细胞均未在很大程度上修复DNA交联。这些数据表明，DNA链间交联的程度或持续性差异并非MMC及其类似物对B淋巴细胞系和T淋巴细胞系细胞产生不同毒性的原因。相反，不同的药物毒性涉及B淋巴瘤细胞早期大量进入凋亡，而T淋巴瘤细胞凋亡诱导延迟且程度最小。
