TX-1877 - DESIGN, SYNTHESIS, AND BIOLOGICAL-ACTIVITIES AS A BRM-FUNCTIONAL HYPOXIC CELL RADIOSENSITIZER

Purpose: 2-Nitroimidazole acetamide TX-1877 and its derivatives (TX-18 77 analogs) were designed, synthesized, and evaluated by their in vitr o and in vivo radiosensitization, tumor growth control, suppression of lung metastasis, and immunopotentiation, as biological response modif ier (IBRM)-functional hypoxic cell radiosensitizers. Materials and Met hods: TX-1877 analogs were designed and synthesized in our laboratory. In: vitro radiosensitizing ability was estimated using EMT6/KU cells under hypoxic conditions. In vivo radiosensitization, antimetastasis, and immunopotentiation were evaluated using female C3H/He mice bearing the SCCVII tumor. Days (15 or 10) after the inoculation of 105 SCCVII tumor cells into the hinder thigh, a drug (0.4 mg/g) was administered i.p. and local irradiation of 30 Gy was given at 30 min after its adm inistration. Tumor growth was observed for 20 days and mice were eutha nized to count the number of metastatic nodules on the surface of the lungs. Tumor tissues were extirpated and stained by the ABC method at 1, 2, and 3 weeks after treatment for immunological evaluation.Results : Novel types of bifunctional radiosensitizers, TX-1877 and its analog s possessing BRM-functions (i.e., antimetastatic and immunopotentiatio n effects) were developed. In vitro radiosensitizing abilities of TX-1 877 and its analogs, with their partition coefficient values of more t han 0.050, were comparable to misonidazole (MISO) at their doses of 1 mM. Tumor regrowth was suppressed evidently 20 days after the treatmen t in the irradiated group with TX-1877 (TX-1877 plus R) and with KIN-8 06 (KIN-806 plus R). The former group reduced markedly the mean number of metastatic lung nodules regardless of radiation therapy. TX-1877 a nd KIN-806 plus R induced helper T lymphocytes. The TX-1877, TX-1877 p lus R, KZN-806, and KIN-806 plus R enhanced macrophage infiltration fo r 3 weeks after treatment. Conclusion: TX-1877 is an excellent BRM-fun ctional hypoxic cell radiosensitizer, expected to be useful for clinic al use. (C) 1998 Elsevier Science Inc.