ENHANCEMENT OF THE EFFECTIVENESS OF METHOTREXATE FOR THE TREATMENT OFSOLID TUMORS BY APPLICATION OF LOCAL HYPERTHERMIA

Investigations were performed to assess the influence of hyperthermia on the pharmacokinetics of a chemotherapeutic drug and on the effectiv eness of combined treatments for induction of tumour cell death and gr owth delay of experimental tumours. Treatments consisted of methotrexa te (MTX, 20 mg/kg ip), hyperthermia at 43 degrees C during 60 min (HT6 0) or 90 min (HT90) and combined chemo-hyperthermia using various time intervals up to 24 h. The results indicate that, for MTX + HT90, conc entrations in excess of 0.02 mg/kg are maintained in tumour tissue dur ing at least 22 days, whereas after the other single and combined trea tments, the concentration decreased below this level within 5-8 days. The combinations of MTX + HT90 also were more effective with respect t o tumour growth delay, 26-28 days, and frequency of partial remissions , 75-100%, as compared to the other treatments: 7-12 days and 0-28% re spectively. These observations correlate well with cell survival data. It is concluded that hyperthermia can enhance the effectiveness of MT X and that variation of time-intervals between administration of MTX a nd hyperthermia as well as the duration of the hyperthermic treatment have a great influence on tumour responses. Unfortunately, also toxic effects were induced distantly from the site of local hyperthermic tre atment by the combination of MTX + HT90 which was most effective with respect to tumour eradication.