Enhancement of the effectiveness of methotrexate for the treatment of solid tumours by application of local hyperthermia

Abstract

Investigations were performed to assess the influence of hyperthermia on the pharmacokinetics of a chemotherapeutic drug and on the effectiveness of combined treatments for induction of tumour cell death and growth delay of experimental tumours. Treatments consisted of methotrexate (MTX, 20 mg/kg ip), hyperthermia at 43°C during 60 min (HT₆₀) or 90 min (HT₉₀) and combined chemo-hyperthermia using various time intervals up to 24 h. The results indicate that, for MTX + HT₉₀, concentrations in excess of 0·02 mg/kg are maintained in tumour tissue during at least 22 days, whereas after the other single and combined treatments, the concentration decreased below this level within 5–8 days. The combinations of MTX + HT₉₀ also were more effective with respect to 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% respectively. These observations correlate well with cell survival data. It is concluded that hyperthermia can enhance the effectiveness of MTX and that variation of time-intervals between administration of MTX and 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 treatment by the combination of MTX + HT₉₀ which was most effective with respect to tumour eradication.

Key Words:

• Methotrexate
• local hyperthermia
• pharmacokinetics
• tumour responses
• clonogenicity