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

为了设计慢生长/低氧细胞导向的多功能抗肿瘤药物，我们设计了2-硝基咪唑乙酰胺类化合物，作为生物反应调节剂(BRM)功能性低氧细胞放射增敏剂，合成并评价了它们的放射增敏、肿瘤生长控制、抑制肺转移和免疫增强等活性。方法和材料：自行设计、合成了2-硝基咪唑乙酰胺类化合物。采用EMT6/KU细胞在低氧条件下进行体外放射增敏实验。根据将细胞存活率降低到1%所需的辐射剂量比，确定1 mm处的增强率(ER)。放射增敏、肿瘤生长控制、抑制肺转移和免疫增强的体内试验评价如下。选用雌性C3H/He小鼠和SCCVII肿瘤细胞。在动物体内接种10^5SCCVII肿瘤细胞15天后，…剂量为40Gy.局部照射时会出现更多红色。各用药组均于用药前30min给予药物(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，ABC法染色进行免疫学评价。结果：KIN-806、TX-1877(亲水性强于其先导的KIN-806)及其类似物等几乎所有的2-硝基咪唑乙酰胺类药物在体外均具有与咪唑相当的放射增敏作用。照射后第20天，TX-1877加放疗(R)组和806加R组明显抑制肿瘤再生长。前一组无论放疗与否，均明显抑制照射后20天肺转移结节的平均数。对肿瘤转移的抑制作用强于KIN-806组。TX-1877和KIN-806加R诱导的辅助性T细胞。1877、1877+R、806、806+R组治疗后1~3周巨噬细胞浸润增加。结论：TX-1877是一种优良的BRM功能缺氧细胞放射增敏剂，有望成为临床实用的多功能缺氧细胞放射增敏剂。较少

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