Petrinelli P, Elli R, Marcucci L, Barbieri C, Ambra R, Antonelli A
Dipartimento di Biopatologia Umana, Università La Sapienza, Rome, Italy.
Carcinogenesis. 1996 Feb;17(2):203-7. doi: 10.1093/carcin/17.2.203.
Ataxia telangiectasia (AT) patients show variable degrees of immunodeficiency and a higher than normal predisposition to lymphoid malignancies. AT cells are characterized by spontaneous chromosome instability resulting in chromosome breakage and in non random chromosome rearrangements. Sequential cytogenetic studies on T-lymphocytes from an AT patient showed the progressive development of a clone bearing a tandem translocation t(14;14)(q11;q32). The abnormal clone had spontaneous chromosome rearrangements. Compared to non clonal cells, the abnormal clone displayed a higher frequency of spontaneous chromosome rearrangements. In only the clonal cells we observed two particular and predominant rearrangements: isodicentric chromosomes and telomeric associations which may derive from faulty recombination. Chromosome instability induced by the etoposide VP16, a DNA topoisomerase II inhibitor, was evaluated in terms of chromosome breakage and SCE frequency. T-lymphocytes from the AT patient showed hypersensitivity to VP16 significantly higher than normal T-lymphocytes. The chromosome instability induced by VP16 is significantly higher in clonal than in non clonal cells, whilst the chromosome instability induced by the radiomimetic drug bleomycin is not significantly different in the two AT lymphocyte subpopulations. The different spontaneous chromosome instability in clonal and non clonal cells together with their different behavior after treatment with only VP16, suggest that clonal cells bearing the tandem translocation could have increased faulty recombination. Given the presence of translocations t(14;14)(q11;q32) in T-prolymphocytic leukemias and T-cell tumors of non AT patients, our findings suggest that VP16 could be considered an antineoplastic treatment particularly indicated in these patients.
共济失调毛细血管扩张症（AT）患者表现出不同程度的免疫缺陷，且患淋巴系统恶性肿瘤的倾向高于正常水平。AT细胞的特征是自发染色体不稳定，导致染色体断裂和非随机染色体重排。对一名AT患者的T淋巴细胞进行的连续细胞遗传学研究显示，一个携带串联易位t(14;14)(q11;q32)的克隆逐渐发展。异常克隆具有自发染色体重排。与非克隆细胞相比，异常克隆显示出自发染色体重排的频率更高。仅在克隆细胞中，我们观察到两种特殊且主要的重排：等臂双着丝粒染色体和端粒联合，这可能源于错误的重组。通过DNA拓扑异构酶II抑制剂依托泊苷VP16诱导的染色体不稳定，根据染色体断裂和姐妹染色单体交换频率进行评估。来自AT患者的T淋巴细胞对VP16的敏感性显著高于正常T淋巴细胞。VP16诱导的染色体不稳定在克隆细胞中显著高于非克隆细胞，而放射模拟药物博来霉素诱导的染色体不稳定在两个AT淋巴细胞亚群中没有显著差异。克隆细胞和非克隆细胞中不同的自发染色体不稳定以及它们仅用VP16处理后的不同行为，表明携带串联易位的克隆细胞可能增加了错误的重组。鉴于在非AT患者的T原淋巴细胞白血病和T细胞肿瘤中存在易位t(14;14)(q11;q32)，我们的研究结果表明VP16可被视为一种抗肿瘤治疗方法，尤其适用于这些患者。
