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

具有5-氟尿嘧啶释放能力的放射解还原激活前药：对小鼠肿瘤的放射增敏作用

• 批准号: 09557069
• 负责人: NISHIMOTO Sei-ichi
• 金额: $ 7.62万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557069/
• 关键词: Radiation Activating Prodrug; Radiolytic Reduction; 5-Fluorouracil; 2-Oxoalkyl Substituted Derivatives; Cytotoxicity; Pharmacokinetics; Intracellular Drug Release; in vivo Sensitzing Effect; 放射線活性化プロドラック; N(1)-C(5)結合ニ量体

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

研究了由5-氟尿嘧啶（5 FU）和N1处的2-氧代烷基取代基组成的辐射还原活化前药，其显示无抗肿瘤活性，但在照射后在缺氧细胞内释放作为良好指定的抗肿瘤剂的5 FU，以获得癌症放射治疗的构效关系。以下是用于确定其临床应用潜力的几种试验的结果。(1)在一系列辐射分解还原活化前药中，大规模合成了几种带有某些2-氧代烷基取代基的5 FU衍生物，其在辐射化学测定中显示出更高的5 FU释放反应性，以提交用于使用小鼠肿瘤的体内测定。(2)评价悬浮在预照射（7.5-22.5戈伊）培养基中的SCCVII肿瘤细胞的存活分数以与孵育时间相关，由此获得细胞毒性与释放的5 FU量之间的定量关系。(3)细胞毒性 ...更多信息 并在氧和缺氧条件下评价前药剂量对SCCVII肿瘤细胞的体外放射增敏活性，其与照射后释放的细胞内5 FU浓度相关。从体外实验数据中得到的结构-细胞毒性和结构-活性关系被用作分子设计和合成研究的指导原则。(4)评价了一系列前药的IC_（250）_（(5)使用携带SCCVII或EMT 6实体瘤的小鼠进行药代动力学分析以评估静脉内注射后血浆和肿瘤组织中的药物浓度。还分析了在不同照射时间下释放的5 FU的时间依赖性肿瘤浓度，从而与前药的5 FU释放能力相关。这些分析提供了一个指导原则，分子设计更好的前药的药代动力学特性。少

项目成果

Dai, W.-M.; Li, Q.; Fong, K.-C.; Chow, C.-W.; Zhou, l.; Hamaguchi, W.; Nishimoto, S: "Remarkable Tethering Effect on DNA Cleavage of Propargylic Sulfone Conjugates with Intercalating Moieties"BioMed Chem. Lett. 8. 169-174 (1998)

戴，W.-M.；

西本精一: "Stereoisomeric C5-C5′-Linked Dihydrothymine Dimers produced by Radiolytic One-Electron Reduction of Thymine Derivatives in Anoxic Aqueous Solution : Structural Characteristics in Reference to Cyclobutane Photodimers" Journal of Organic Chemistry. 6

Seiichi Nishimoto：“缺氧水溶液中胸腺嘧啶衍生物的放射解单电子还原产生的立体异构 C5-C5-连接二氢胸腺嘧啶二聚体：环丁烷光二聚体的结构特征”有机化学杂志 6。

芝本雄太: "The influence of DNA Ploidy of a Human Tumor Cell Line on the Frequencies of Micronuclei or Chromosome Aberrations after Irradiation"Mutation Research. 418. 49-57 (1998)

Yuta Shibamoto：“人类肿瘤细胞系 DNA 倍性对辐射后微核或染色体畸变频率的影响”突变研究 418. 49-57 (1998)。

芝本雄太: "Absence of Thoracic Radiation Myelitis after Hyperfractionated Radiation Therapy with and without Concurrent Chemotherapy for Stage III Non-Small-Cell Lung Cancer"International Journal of Radiation Oncology・Biology・physics. 40. 343-346 (1998)

Yuta Shibamoto：“III 期非小细胞肺癌超分割放射治疗联合或不联合化疗后胸部放射性脊髓炎的消失”国际放射肿瘤学·生物学·物理学杂志 40. 343-346 (1998)。

周玲: "Bifunctional 2-Naphthyl Propargylic Sulfones Exhibiting High DNA Intercalating and Alkylatinf Activity"Bioorganic & Medicinal Chemistry Letters. 9. 2789-2794 (1999)

Ling Zhou：“具有高 DNA 嵌入和烷基化活性的双功能 2-萘基炔丙砜”《生物有机与药物化学快报》9. 2789-2794 (1999)。