Biological effects of novel radiation-activated prodrugs of mitomycin C

作为一种新的靶向低氧肿瘤细胞的方法，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，而辐射主要集中在肿瘤上，因此这种前药激活只发生在肿瘤中。在本研究方案中，我们首先考察了5-氟-2‘-脱氧尿苷(FdUrd)的前体药物对N(3)位2-氧代烷基取代的影响。低氧照射后，前药释放FdUrd的G值为1.6~2.0×10~(-7)~(-7)mol/J。低氧照射的FdUrd释放的G值约为有氧照射的100倍。在所测试的前体药物中，含有2-氧环戊基取代基的OFU106在培养基中释放的FdUrd量最高，并进行了进一步的体外和体内检测。OFU106单独作用至0.2 mM时无细胞毒作用，但在低氧照射前与细胞作用24 h后，细胞毒作用增强，以1%的存活分数计算，0.04 mM和0.2 mM时的增殖率分别为1.35~1.4和1.45~1.5。然而，在体内，与单独接受20Gy射线照射相比，在20Gy射线照射前给予OFU106(100或300 mg/kg)并没有产生明显的生长延迟。鉴于这一结果，我们尝试将这一前药设计策略应用于丝裂霉素C。我们合成了一种带有2-氧丙基取代基的丝裂霉素C前药，并考察了其体外作用。但未观察到对低氧细胞的优先毒性。我们将尝试将这一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.