Slow-growth/hypoxic cell-directed design of multifunctional antitumor agents

多功能抗肿瘤药物的慢生长/缺氧细胞定向设计

• 批准号: 08672561
• 负责人: HORI Hitoshi
• 金额: $ 1.34万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08672561/
• 关键词: hypoxic cancer cell; antitumor agents; molecular design; slow-growth; radiosensitizer; nitroimidazole; 分化誘導; アポトーシス; 血管新生

For our slow-growth/hypoxic cell-directed design of multifunctional antitumor agents, we designed 2-nitroimidazole acetamide derivatives, synthesized, and evaluated by their activities of radiosensitization, tumor growth control, suppression of lung metastasis, and immunopotentiation, as biological response modifier (BRM) -functional hypoxic cell radiosensitizers. Methods and materials : 2-Nitroimidazole acetamide derivatives were designed, synthesized in our laboratory. In vitro assay for radiosensitization was measured using EMT6/KU cells under hypoxic conditions. Enhaancement ratio (ER) was determined at 1 mM from the ratio of radiation doses required to reduce the surviving fraction of the cells to 1%. In vivo assay for radiosensitization, tumor growth control, suppression of lung metastasis, and immunopotentiation was evaluated as follows. Female C3H/He mice and SCCVII tumor cells were used. Fifteen days after inoculation of 10^5 SCCVII tumor cell into the animals, 40Gy was delive … More red aslocal irradiation. A drug (0.4 mg/g) was administered 30 min before this treatment to each drug treated group. Tumor growth was observed until day 20. The metastatic nodules on the surface of the lungs taken at day 20 were counted and all tissues were stained by the ABC method for immunological evaluation. Results : Almost 2-nitroimidazole acetamides such as KIN-806, TX-1877 (more hydrophilic than its lead KIN-806), and its analogs, were good radiosensitisers having ER comparable to misonidazole in vitro. The TX-1877 plus radiation (R) group and the 806 plus R group evidently suppressed tumor regrowth at day 20 after irradiation. The former group markedly suppressed the mean number of metastatic lung nodules 20 days after irradiation in regardless of radiation therapy. It inhibited metastasis strongly than the KIN-806 group. TX-1877 and KIN-806 plus R induced helper T lymphocytes. The 1877,1877 plus R,806, and 806 plus R groups, enhanced the macrophage infiltration from week 1 to week 3 after treatment. Conclusion : TX-1877 is an excellent BRM-functional hypoxic cell radiosensitizer, and expected to be useful multifunctional hypoxic cell radiosensitizer for clinical use. Less

对于我们的多功能抗肿瘤药物的缓慢生长/缺氧细胞定向设计，我们设计了2-硝基咪唑乙酰胺衍生物，合成并通过其放射增敏、肿瘤生长控制、抑制肺转移和免疫增强的活性进行评估，作为生物反应调节剂（BRM）功能性缺氧细胞放射增敏剂。方法和材料：本实验室设计、合成了2-硝基咪唑乙酰胺衍生物。在缺氧条件下使用 EMT6/KU 细胞测量体外放射增敏试验。根据将细胞存活率降低至 1% 所需的辐射剂量比率，确定 1 mM 的增强比 (ER)。如下评估放射增敏、肿瘤生长控制、肺转移抑制和免疫增强的体内测定。使用雌性C3H/He小鼠和SCCVII肿瘤细胞。将 10^5 SCCVII 肿瘤细胞接种到动物体内 15 天后，进行 40Gy 的红色局部照射。在此治疗前30分钟向每个药物治疗组施用药物(0.4mg/g)。观察肿瘤生长直至第20天。第20天取肺表面转移结节计数，所有组织采用ABC法染色进行免疫学评价。结果：几乎所有2-硝基咪唑乙酰胺，如KIN-806、TX-1877（比其先导KIN-806更亲水）及其类似物，都是良好的放射增敏剂，其体外ER与米索硝唑相当。 TX-1877加辐射(R)组和806加R组在辐射后第20天明显抑制肿瘤再生。无论采用哪种放射治疗，前一组在照射后 20 天均显着抑制了肺转移结节的平均数量。其对转移的抑制作用强于KIN-806组。 TX-1877 和 KIN-806 加 R 诱导辅助 T 淋巴细胞。 1877、1877加R、806和806加R组在治疗后第1周至第3周增强了巨噬细胞浸润。结论：TX-1877是一种优良的BRM功能性缺氧细胞放射增敏剂，有望成为临床实用的多功能缺氧细胞放射增敏剂。较少的

项目成果

H.Hori, et al: "Respiratory activities of liver mitochondria,isolated from frehwater furtle Chinemgs reuesii as anexperimental ahoxia tolerent..." Pathoplysiology. 4. 183-190 (1997)

H.Hori 等人：“从淡水富特 Chinemgs reuesii 中分离出的肝线粒体的呼吸活动，作为实验性缺氧耐受......”病理学。

S.Masunaga, H.Hori, et al: "Effects of Bioreductive Agents,Tirapazamine and Mitomycinc on Quiescent Cell Pooulation in Solid Tumors Ecaluatedby" Jpn.J.,Cancer Res.88. 907-914 (1997)

S.Masunaga、H.Hori 等人：“生物还原剂、替拉扎明和丝裂霉素对实体瘤中静止细胞群的影响评估”Jpn.J.，Cancer Res.88。

Hori, Hitoshi, Tatsuya Fujimoto, Hideakira Yokoyama, Ning Pan, and Miki Kurosaki.: "Respiratory activities of liver mitochondria, isolated from freshwater turtle Chinemys revesii as an experimental anoxia tolerant model system, determined by mitochondrial

Hori、Hitoshi、Tatsuya Fujimoto、Hideakira Yokoyama、Ning Pan 和 Miki Kurosaki。：“从淡水龟 Chinemys revesii 中分离出的肝脏线粒体的呼吸活动，作为实验性耐缺氧模型系统，由线粒体确定

H.Hori: "Election-Atfinic N-Thiadiazolylanilines:Design of Mitochondical Cytofoxin with Antitunor Activity" Proc.5th Koren-Japan Joiut Symg on Drug Dosign & Development. 81-90 (1996)

H.Hori：“Election-Atfinic N-Thiadiazolylanilines：具有抗肿瘤活性的线粒体细胞毒素的设计”Proc.5th Koren-Japan Joiut Symg on Drug Dosign

H.Hori, et al: "Design and Sgnthesis of New Mitochondrial Cytotoxin N-Thiadiazalyl-anilines Showing Inhibitory Activities of Tumor Cell Growth" Bioorganie and Medicinal Chemistry. 4・2. 247-253 (1996)

H.Hori 等人：“显示肿瘤细胞生长抑制活性的新型线粒体细胞毒素 N-噻二唑基-苯胺的设计和合成”《生物有机和药物化学》247-253。