Manome Y, Wen P Y, Dong Y, Tanaka T, Mitchell B S, Kufe D W, Fine H A
Division of Cancer Pharmacology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
Nat Med. 1996 May;2(5):567-73. doi: 10.1038/nm0596-567.
Cytosine arabinoside (ara-C) is a cytidine analog that incorporates into replicating DNA and induces lethal DNA strand breaks. Although ara-C is a potent antitumor agent for hematologic malignancies, it has only minimal activity against most solid tumors. The rate-limiting step in intracellular ara-C activation is phosphorylation of the prodrug by deoxycytidine kinase (dCK). The present results demonstrate that both retroviral and adenoviral vector-mediated transduction of the dCK cDNA results in marked sensitization of glioma cells lines to the cytotoxic effects of ara-C in vitro. We also demonstrate that ara-C treatment of established intradermal and intracerebral gliomas transduced with dCK results in significant antitumor effects in vivo. These data suggest that viral vector transduction of the dCK gene followed by treatment with ara-C represents a new chemosensitization strategy for cancer gene therapy.
阿糖胞苷（ara-C）是一种胞苷类似物，可掺入正在复制的DNA中并诱导致命的DNA链断裂。尽管阿糖胞苷是治疗血液系统恶性肿瘤的有效抗肿瘤药物，但它对大多数实体瘤的活性极小。细胞内阿糖胞苷激活的限速步骤是前药被脱氧胞苷激酶（dCK）磷酸化。目前的结果表明，逆转录病毒和腺病毒载体介导的dCK cDNA转导均导致胶质瘤细胞系在体外对阿糖胞苷的细胞毒性作用明显敏感。我们还证明，用阿糖胞苷处理经dCK转导的已建立的皮内和脑内胶质瘤在体内产生显著的抗肿瘤作用。这些数据表明，dCK基因的病毒载体转导后再用阿糖胞苷治疗代表了一种用于癌症基因治疗的新的化学增敏策略。
