Effects of temperature on the therapeutic efficacy and pharmacokinetics of ifosfamide.

The influence of tumor temperature (28, 32, 37, 39, 41, or 43 degrees C for 1 h) on the therapeutic efficacy of i.v. single bolus injections of ifosfamide (IFO) (32, 65, 125, or 250 mg/kg body weight) in human tumor xenografts (MX1 breast carcinoma) grown in nude mice (n = 240) was studied. Tumor temperature was controlled by water bath immersion. Sixty days after treatment the percentage of tumor-free survival was determined. For example, at 37 degrees C IFO in a dose of 65 mg/kg body weight led to 10% tumor-free survival in the treated animals. At 43 degrees C the same dose resulted in 60% tumor-free survival. A clear drug dose- and temperature-dependent increase of the therapeutic efficacy of an active oxazaphosphorine compound was also demonstrated in vitro. The concentrations of IFO and of 4-hydroxyifosfamide in blood and tumors at different body temperatures (controlled by water bath immersion) were determined over 120 min and WBC counts were obtained. The half-lives and the areas under the curve for IFO in blood were not significantly different at 37 degrees C and 41 degrees C. Since the half-life of IFO depends mainly on hepatic metabolism, the similarity of half-lives and of areas under the curve for IFO at 37 degrees C and 41 degrees C indicates a constant activation rate. However, significantly lower plasma concentrations of the activated drug at a liver (body) temperature of 41 degrees C, compared with 37 degrees C, were found, indicating a higher elimination rate. The concentration of the activated drug in the tumors within the initial 60 min at 41 degrees C, however, exceeded by > 2-fold that at 37 degrees C. The bone marrow toxicity of the same drug dose did not significantly increase with body temperature.

Local hyperthermia enhances cyclophosphamide, ifosfamide and cis-diamminedichloroplatinum cytotoxicity on human-derived breast carcinoma and sarcoma xenografts in nude mice.

Antitumour response and toxicity of locally applied hyperthermia with or without cyclophosphamide, ifosfamide, and cis-diamminedichloroplatinum (cisplatin) have been compared. The model systems were human breast carcinoma (MX1/3) and human sarcoma (S117) grown in nude mice. In order to detect changes of tumour oxygenation intratumoral PO2 and pH were measured before, during and following hyperthermia. In both human tumour lines a monotherapy with one of the cytotoxic drugs or with hyperthermia caused a transient growth delay, while the combination of the same dose of the drugs with hyperthermia (at 43 degrees C for 1 h) resulted in complete tumour remissions. During hyperthermia, in both tumour types oxygenation was improved. Intratumoral pH remained practically unchanged.