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Interactions of hyperthermia and chemotherapy in animals.

In tissue culture, the cytotoxicity of a number of commonly used chemotherapeutic drugs is greatly enhanced at elevated temperatures. However, pharmacokinetics, drug concentrations, oxygen tension, and pH in tumors in animals can all vary widely from those in cell cultures. In addition, tissue culture studies do not give vital information on the effect of combinations of drugs and hyperthermia on normal tissues or metastases. Available studies of drugs and hyperthermia in animals are reviewed, and they yield clinically useful information. One study indicated that the activity of methotrexate was not enhanced by hyperthermia in vivo . Results for alkylating agents were not conclusive. Antitumor effects of 1,3-bis(2-chloroethyl)-1-nitrosourea, bleomycin, and cis -diamminedichloroplatinum, however, were significantly potentiated by local hyperthermia. 1,3-bis(2-chloroethyl)-1-nitrosourea effects were enhanced between 41 and 42°C, and thus, it is potentially of use in the setting of systemic hyperthermia. Bleomycin, however, was enhanced significantly only near 43°, suggesting that its clinical use is more appropriate with local hyperthermia. Adriamycin and S -(2-aminoethyl)isothiouronium dihydrobromide, although potentiated in vitro , were not potentiated in vivo in doses which were clinically tolerable. Discrepancies between the in vitro and in vivo findings are likely due, at least in part, to differences in drug concentration. The combination of local primary tumor hyperthermia and chemotherapy did not adversely affect the incidence or severity of spontaneous lung metastases in KHT tumor-bearing mice.

Very few studies of the pharmacology of drugs in vivo in the presence of hyperthermia have been reported. Uptake of chemotherapeutic drugs may be enhanced in hyperthermic tissue. Further in vivo studies both of effectiveness and drug pharmacology for combined hyperthermia and chemotherapy are advisable to define optimum time-dose schedules for clinical trials.