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Biological effects of novel radiation-activated prodrugs of mitomycin C

新型辐射激活丝裂霉素C前药的生物学效应

基本信息

批准号：
14370276
负责人：
SHIBAMOTO Yuta
金额：
$ 2.43万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

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.

作为一种靶向缺氧肿瘤细胞的新方法，我们研究了通过捕获水合电子在缺氧照射下激活的抗肿瘤前药。由于缺氧几乎只存在于肿瘤中，而辐射集中在肿瘤上，所以这种药物前激活只发生在肿瘤中。在本研究计划中，我们首先研究了在N(3)位置上具有2-氧烷基取代基的5-氟-2'-脱氧尿苷（FdUrd）的前药的影响。低氧辐照后，前药释放FdUrd的g值为1.6 ~ 2.0 × 10^<-7> mol/J。低氧辐照释放FdUrd的g值约为好氧辐照的100倍。在测试的前药中，含有2-氧环戊基取代基的OFU106在培养基中释放的FdUrd量最高，并对其进行了进一步的体外和体内检测。尽管OFU106独自管理没有细胞毒性的浓度为0.2毫米,它产生一个增强的细胞毒性效应当admiistered缺氧辐照和保持细胞24 h。增强比率计算的幸存的分数1% 1.35 -1.4 0.2 -1.5 0.04毫米和1.45毫米。体内,然而OFU106管理局(100或300毫克/公斤)前20 Gy辐照没有产生显著增长的延误而独自20 Gy的辐射。鉴于这一结果，我们尝试将这种前药设计策略应用于丝裂霉素C。我们合成了含有2-氧丙基取代基的丝裂霉素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。我们将尝试将这一策略应用于其他更有效的抗癌药物。