Enhancement of misonidazole chemosensitization effect by mild local hyperthermia

In an attempt to increase the chemosensitization effect of the alkylating agents 1,3 bis(2-chloroethyl)-1-nitrosourea (BCNU) and cyclophosphamide (CY), by misonidazole (MISO) at the tumor site, mild hyperthermic treatment (41.5 degrees C, 1 hr) was applied at various administration sequences. C3Hf/Sed mice bearing subcutaneous FSa-II tumors in the foot were used for a tumor growth time assay. Local hyperthermic treatment increased the antitumor activities of BCNU and CY by 1.4 and 2.4 fold, respectively. MISO at 2.5 mmole/kg potentiated the antitumor activities of BCNU, but not CY, at normal body temperature. There were no significant improvement of MISO chemosensitization when heat was given before the administration of BCNU and CY. However, a significant enhancement of chemosensitization was observed when heat was given after the administration of MISO and the alkylating agents. Enhancement ratios of about 2.4 and 4.7 were observed with BCNU and CY, respectively. There may be two mechanisms responsible for this thermal enhancement. First, the MISO pre-incubation time that was required for the expression of chemosensitization effect decreased substantially at elevated temperatures. This hypothesis was supported by the pharmacokinetic studies that MISO was rapidly eliminated from tumors in the first 10 min during the local heat treatment and remained at a plateau with a concentration of about 5-fold less than the peak MISO concentration in the control tumors. This rapid elimination might result from the increase in the rate of hypoxic metabolism of MISO in heated tumors. Second, heat may increase the MISO-alkylating agent interactions, which are independent of pre-incubation time. This effect was especially pronounced in CY because pre-incubation-induced chemosensitization of CY in unheated tumor was insignificant in this study. The significant improvement of MISO chemosensitization at moderately elevated temperatures can be useful clinically in combined hyperthermia and chemotherapy treatment.