| Research Abstract |
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
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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
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