Biological effects of novel radiation-activated prodrugs of mitomycin C

作为一种靶向低氧肿瘤细胞的新方法，我们研究了通过捕获水合电子而被低氧辐射激活的抗肿瘤前药。由于缺氧几乎只存在于肿瘤中，并且辐射集中在肿瘤上，因此这种前药活化仅发生在肿瘤中。在本研究中，我们首先研究了N（3）位带有2-氧代烷基取代基的5-氟-2 '-脱氧尿苷（FdUrd）前药的作用。在低氧照射后，前药以1.6-2.0 x 10 μ mol/J的G值释放FdUrd<-7>。缺氧照射的FdUrd释放的G值比有氧照射的高约100倍。在所测试的前药中，带有2-氧代环戊基取代基的OFU 106在培养基中释放最高量的FdUrd，并对其进行进一步的体外和体内测定。尽管单独施用0 FU 106在浓度高达0.2mM时没有显示出细胞毒性，但当在低氧照射前施用并与细胞保持24小时时，其产生增强的细胞毒性效应。在0.04 mM和0.2 mM时，在存活分数为1%时计算的增强比分别为1.35-1.4和1.45-1.5。然而，在体内，与单独20戈伊辐射相比，在20戈伊辐射之前给予OFU 106（100或300 mg/kg）并没有产生显著的生长延迟。鉴于这一结果，我们随后尝试将这种前药设计策略应用于丝裂霉素C。我们合成了一个2-氧丙基取代的丝裂霉素C前药，并研究了其体外作用。然而，没有观察到对缺氧细胞的优先毒性。我们将尝试将这种策略应用于其他更有效的抗癌药物。

As a novel method of targeting hypoxic tumor cells, we have investigated antitumor prodrugs that are activated by hypoxic irradiation through capturing of hydrated electrons. Since hypoxia exists almost exclusively in tumors and radiation is focused on the tumor, this prodrug activation occurs only in tumors. In this research programwe first investigated the effects of prodrugs of 5- fluoro-2'-deoxyuridine (FdUrd) with 2-oxoalkyl substituents at the N(3) position. The prodrugs released FdUrd at G-values of 1.6-2.0 x 10^<-7> mol/J following hypoxic irradiation. The G-values for FdUrd release with hypoxic irradiation were about 100-fold higher than those with aerobic irradiation. Among the prodrugs tested, OFU106 bearing a 2-oxocyclopentyl substituent released the highest amount of FdUrd in the culture medium, and it was subjected to further in vitro a in vivo assays. Although OFU106 administered alone showed no cytotoxicity up to a concentration of 0.2 mM, it produced an enhanced cytotoxic effect when admiistered before hypoxic irradiation and kept with the cells for 24 h. The enhancement ratios calculated at the surviving fraction of 1% were 1.35-1.4 at 0.04 mM and 1.45-1.5 at 0.2 mM. In vivo, however administration of OFU106 (100 or 300 mg/kg) before 20 Gy of irradiation did not produce marked growth delays compared with 20 Gy of radiation alone. In view of this result, we then tried to apply this strategy of prodrug design to mitomycin C. We synthesized a prodrug of mitomycin C with a 2-oxopropyl substituent and investigated its in vitro effects. However, preferential toxicity towards hypoxic cells was not observed. We will try to apply this strategy to other more potent anticancer agents.