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

在我们的慢生长/缺氧细胞导向的多功能抗肿瘤药物设计中，我们设计了2-硝基咪唑乙酰胺衍生物，作为生物反应调节剂(BRM) -功能性缺氧细胞放射增敏剂，合成并评估了其放射增敏、肿瘤生长控制、肺转移抑制和免疫增强的活性。方法与材料：设计并合成了2-硝基咪唑乙酰胺衍生物。使用缺氧条件下的EMT6/KU细胞进行体外放射致敏试验。增强比（ER）从使细胞存活率降低到1%所需的辐射剂量比测定为1mm。放射增敏、肿瘤生长控制、肺转移抑制和免疫增强的体内实验评估如下。使用雌性C3H/He小鼠和SCCVII肿瘤细胞。10^5个SCCVII肿瘤细胞接种于动物体内15天后，局部照射40Gy。治疗前30 min给药0.4 mg/g。观察肿瘤生长至第20天。计数第20天取肺表面转移结节，并用ABC法对所有组织进行免疫染色。结果：2-硝基咪唑类乙酰胺如KIN-806、TX-1877（亲水性优于KIN-806）及其类似物均为较好的放射增敏剂，体外ER与米索硝唑相当。x -1877加放疗组和806加放疗组在放疗后第20天明显抑制肿瘤再生。前一组在放射治疗后20天显著抑制了肺转移结节的平均数量。与KIN-806组相比，其对肿瘤转移的抑制作用较强。TX-1877和KIN-806 + R诱导辅助T淋巴细胞。1877、1877 + R、806、806 + R组治疗后第1 ~ 3周，巨噬细胞浸润增强。结论：TX-1877是一种优良的brm功能缺氧细胞放射增敏剂，有望成为临床有用的多功能缺氧细胞放射增敏剂。少

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