title: 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 degrees 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.
authors.affiliation: Laboratory for Radiobiology, University of Amsterdam, The Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: Schopman
authors.forename: C
authors.initials: C
authors.lastname: Van Bree
authors.forename: J B
authors.initials: JB
authors.lastname: Kipp
authors.forename: G W
authors.initials: GW
authors.lastname: Barendsen
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001772:Blood Cell Count / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects; D003131:Combined Modality Therapy; D005260:Female; D006979:Hyperthermia, Induced; D008727:Methotrexate / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D010976:Platelet Count / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate