Gregoire V, Hittelman W N, Rosier J F, Milas L
St-Luc University Hospital, Department of Radiation Oncology, 1200 Brussels, Belgium.
Oncol Rep. 1999 Sep-Oct;6(5):949-57. doi: 10.3892/or.6.5.949.
The available knowledge on potential radiosensitizing nucleoside analogues with special focus on fludarabine and gemcitabine is reviewed. These analogues are prodrugs whose active triphosphate forms inhibit various enzymes involved in DNA synthesis and repair. Several properties of these analogues support their use as radiosensitizers. As repair inhibitors, they have the potential to increase the amount of residual DNA and chromosome damage after irradiation, and as DNA synthesis inhibitors, they specifically target the S-phase cell component and could thus overcome the detrimental effect of tumor clonogen repopulation during fractionated irradiation. Also, through their cytotoxic effect, these analogues could increase tumor cell loss, facilitating tumor reoxygenation, and thus obviate tumor hypoxia's inhibitory effect on radioresponse. Induction of DNA damage in all phases of the cell cycle by irradiation could create DNA sites for drug incorporation, possibly inducing an apoptotic response in cells outside of S-phase. Experimental data addressing these hypotheses are reviewed and updates on ongoing clinical trials combining fludarabine or gemcitabine and irradiation are given.
本文综述了关于潜在放射增敏核苷类似物的现有知识，特别关注氟达拉滨和吉西他滨。这些类似物是前药，其活性三磷酸形式可抑制参与DNA合成和修复的各种酶。这些类似物的若干特性支持它们用作放射增敏剂。作为修复抑制剂，它们有可能增加照射后残留的DNA量和染色体损伤，而作为DNA合成抑制剂，它们特异性靶向S期细胞成分，从而可以克服分次照射期间肿瘤克隆原细胞再增殖的有害影响。此外，通过其细胞毒性作用，这些类似物可增加肿瘤细胞丢失，促进肿瘤再氧合，从而消除肿瘤缺氧对放射反应的抑制作用。照射在细胞周期的所有阶段诱导DNA损伤可产生药物掺入的DNA位点，可能诱导S期以外细胞的凋亡反应。本文回顾了针对这些假设的实验数据，并给出了关于正在进行的联合氟达拉滨或吉西他滨与照射的临床试验的最新情况。
