Manome Y, Weichselbaum R R, Kufe D W, Fine H A
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School Boston, MA.
Oncol Res. 1993;5(3):139-44.
1-beta-D-Arabinofuranosylcytosine (ara-C) is an anti-leukemic agent that incorporates into cellular DNA leading to inhibition of DNA synthesis and loss of clonogenic survival. In contrast, ionizing radiation induces DNA damage through the generation of reactive oxygen intermediates. Although little is known of the specific determinants of ara-C and ionizing radiation-induced cytotoxicity, recent work has shown that both are capable of inducing internucleosomal DNA fragmentation in a pattern consistent with programmed cell death (apoptosis). In order to assess the importance of apoptosis in drug and ionizing radiation-induced cytotoxicity in the U-937 myelomonocytic cell line, we created cell lines that constitutively express a transfected bcl-2 gene. Bcl-2 was capable of inhibiting 40-50% of the ara-C and ionizing radiation-induced internucleosomal DNA fragmentation at all tested concentrations. However, cell survival following exposure to these agents was only increased in the bcl-2 transfectants at relatively low doses of ara-C and ionizing radiation. These data demonstrate that although bcl-2 is capable of inhibiting ara-C and ionizing radiation-induced DNA fragmentation in myeloid cells, it increases cell survival only at low doses of these agents. This suggests that apoptosis may be a less important mechanism of cytotoxicity at higher doses of ara-C and ionizing radiation than it is at lower doses.
1-β-D-阿拉伯呋喃糖基胞嘧啶（阿糖胞苷，ara-C）是一种抗白血病药物，它可掺入细胞DNA，导致DNA合成抑制和克隆源性存活丧失。相比之下，电离辐射通过产生活性氧中间体诱导DNA损伤。尽管对于阿糖胞苷和电离辐射诱导的细胞毒性的具体决定因素了解甚少，但最近的研究表明，两者都能够以与程序性细胞死亡（凋亡）一致的模式诱导核小体间DNA片段化。为了评估凋亡在U-937髓单核细胞系中药物和电离辐射诱导的细胞毒性中的重要性，我们构建了组成性表达转染bcl-2基因的细胞系。在所有测试浓度下，Bcl-2能够抑制40%-50%的阿糖胞苷和电离辐射诱导的核小体间DNA片段化。然而，在相对低剂量的阿糖胞苷和电离辐射下，暴露于这些药物后的细胞存活仅在bcl-2转染子中增加。这些数据表明，尽管Bcl-2能够抑制髓细胞中阿糖胞苷和电离辐射诱导的DNA片段化，但它仅在低剂量的这些药物下增加细胞存活。这表明，在高剂量的阿糖胞苷和电离辐射下，凋亡可能比在低剂量下是一种不太重要的细胞毒性机制。
