1995 Volume 11 Issue 1 Pages 21-28
The cytotoxicity of some chemotherapeutic agents are enhanced at elevated temperatures in vitro and in vivo. It was reported misonidazole (MISO), a hypoxic cell radiosensitizer, can also act as a heatsensitizer and chemosensitizer. We investigated the multimodal effects of AK-2123, a 3-nitrotriazole derivative, using transplanted tumors in mice. Injections of AK-2123 (200mg/kg or 400mg/kg, i. p.) prior to X-irradiation or local hyperthermia enhanced the growth delay of tumor induced by X-irradiation with 15 Gy or hyperthermia (43°C, 30min.) alone. AK-2123 was also effective on thermo-chemotherapy with CDDP. Blood flow reduction was observed in tumors by AK-2123 administration. The relative concentration of CDDP in locally heated tumor was reduced to 25 % that of the controls when assessed 5 hours after hyperthermia by atomic absorption analysis, but it recovered to half the level of the nonheated controls by AK-2123 (400mg/kg) administration 30 minutes before hyperthermia. We also investigated the multimodality-treatments of a sequential use of a AK-2123 plus a bioreductive agent mitomycin C (MMC) and hydralazine (HDZ) as a vasodilative drug combined with radiothermotherapy on SCC VII tumors. The multimodality-treatment of (AK-2123-MMC) -10Gy/HDZ/HT induced the prolonged tumor doubling time which is as same as 50 Gy alone. Therefore, this multimodality-treatment induced the high dose modifying factor of 5.0. These results suggest that tumor vasculature is much more sensitive to AK-2123 than vasculature of normal tissues and that hyperthermia after AK-2123 administration can induce transient hypoxia and selective reduction of pH in tumor. Futhermore, these phenomena may cause to increase cell killing by bioreductive agent mitomycin C and hyperthermia.
