Radiolytic Reduction Activating Prodrugs Possessing 5-Fluorouracil-Releasing Ability : Radiation Sensitizing Effect on Mouse Tumors

放射性还原激活5-fluorouracil（5 FU）和2-oxoalkyl物质的药物在N1上的作用，因为没有显示出抗剂活性，但释放5 FU作为一种在辐射中的高氧细胞上的良好的特异性抗剂剂，已经研究以获得放射治疗的结构活性关系。以下是一些结果，以确定临床应用的潜力。（1）在一系列的放射性还原激活药物中，携带多种5 FU衍生物的序列2-氧烷基物质，显示出更高的5 FU-释放在辐射化学试验中的反应活性在一个大尺度上合成，以便在体内试验中提交使用小鼠肿瘤的反应。（2）在辐射前（7.5-22.5 Gy）的SCCVII肿瘤细胞的存活片段被搁置到与孵化时间相关的培养中，根据细胞毒性之间的数量关系和5 FU释放的数量关系被发现。（3）细胞毒性。 ... More 并且，向体外放射性敏感化活动的SCCVII肿瘤细胞在药物下评估了氧化和超氧化条件剂量的药物，其中与5 FU释放的放射性相关。结构-细胞毒性和结构-活动关系是从体外数据作为分子设计和合成研究的指导原则衍生出来的。（4） The ICイイD250エD2 values of a series of prodrugs were evaluated to correlate with molecular structures and in vitro radiosensitizing activity。（5） Pharmacokinetic analyses were performed to evaluate drug concentrations in plasma and tumor tissues after i. v. injection， using mice bearing SCCVII or EMT6 solid tumors。5 FU释放的5 FU的时间依赖性itratumor集中也在不同的辐射时间和辐射时间下进行了分析，并与5 FU释放能力相关。这些分析提供了一个指导原则，用于更好的药物分子设计，并尊重药理学特征。Less（低）

Radiolytic reduction activating prodrugs consisting of 5-fluorouracil (5FU) and 2-oxoalkyl substituents at N1, that show no antitumor activity, but release 5FU as a well-specified antitumor agent within hypoxic cells upon irradiation, were studied to obtain a structure-activity relationship for radiotherapy of cancer. The followings are results in the several assays for determining their potential of clinical application.(1) Among a series of radiolytic reduction activating prodrugs, several 5FU derivatives bearing certain 2-oxoalkyl substituents that showed higher 5FU-releasing reactivity in the radiation chemical assay were synthesized on a large scale to submit for in vivo assay using mouse tumors.(2) The survival fractions of SCCVII tumor cells suspended in the pre-irradiated (7.5-22.5 Gy) culture medium were evaluated to correlate with the incubation time, by which a quantitative relationship between the cytotoxicity and the amount of 5FU released was obtained.(3) The cytotoxicity … More and the in vitro radiosensitizing activity toward SCCVII tumor cells were evaluated under oxic and hypoxic conditions dosages of prodrugs, which were correlated with intracelluar concentration of 5FU released upon irradiation. The structure-cytotoxicity and structure-activity relationships derived from the in vitro data were utilized as a guiding principle for molecular design and synthetic study.(4) The ICィイD250ィエD2 values of a series of prodrugs were evaluated to correlate with molecular structures and in vitro radiosensitizing activity.(5) Pharmacokinetic analyses were performed to evaluate drug concentrations in plasma and tumor tissues after i.v. injection, using mice bearing SCCVII or EMT6 solid tumors. The time-dependent itratumor concentrations of 5FU released were also analyzed under various timings of irradiation, thereby correlating with the 5FU-releasing ability of prodrugs. These analyses provided a guiding principle for molecular design of better prodrugs with respect to the pharmacokinetic characteristics. Less