The effect of hyperglycemia on the cytotoxic effect of a chemotherapeutic agent was studied at elevated temperature. The seventh generation of a spontaneous C3Hf/Sed mouse fibrosarcoma, FSa-II, was transplanted into the footpads of the same strain of mice. Hyperthermia was given by immersing animal feet into a water bath where 41.5 +/- 0.1 degrees (range) was maintained by a constant temperature circulator. Cyclophosphamide (CY), an alkylating agent, was selected as a test agent. Single i.p. doses of glucose and of CY were given 60 and 30 min before the initiation of hyperthermia. Tumor response was assayed by determining the median tumor growth time (time required for one-half of the treated tumors to reach 1000 cu mm), and the dose-response curve was obtained. Hyperthermia enhanced tumor response to CY. The enhancement was greater when a glucose dose of 10 mg/g was administered before CY and heat treatments. The enhancement ratio, calculated as a ratio of the tumor growth time following CY (200 mg/kg) with heat or with glucose and heat to that following CY alone, was 1.31 or 2.86, respectively. Glucose given at ambient temperature did not enhance the effect of CY. A dose-response curve obtained for a glucose dose with fixed CY (200 mg/kg) and heat (90 min at 41.5 degrees) doses demonstrated that a significant enhancement was obtained following a glucose dose as low as 2 mg/g, suggesting that the glucose enhancement could be safely achieved for human cancer treatment.