title: Effect of whole body hyperthermia on cis-diamminedichloroplatinum (II)-induced antitumour activity and tissue Pt-distribution: do anaesthetics influence the therapeutic ratio?
abstract: Thermal enhancement of cis-diamminedichloroplatinum (II) (DDP)-mediated antitumour activity and normal tissue toxicities by whole body hyperthermia were compared in a F344 rat model under different anaesthetic conditions. Whole body hyperthermia (WBH: 120 min at 41.5 degrees C) enhanced both DDP-mediated antitumour activity and toxic side-effects. Our present study shows that anaesthetics might influence the thermal enhancement ratios (TER) calculated for DDP-mediated normal tissue toxicity but did not influence the TER calculated for antitumour activity. The TER calculated for DDP-mediated antitumour activity was 2.9. As a result of the anaesthetics used, the TER calculated for kidney and gastrointestinal toxicity ranged from 1.8 to 4.5 and from 1.2 to 2.3, respectively. The TER estimated for DDP-mediated general toxicities varied between 2.9 and 4.0 for weight loss, and from 2.0 to 2.3 based on the LD50. The differential effect of anaesthetics on TER calculated for antitumour activity and normal tissue toxicity led to different therapeutic ratios. For example the therapeutic ratio for combined WBH and DDP, using kidney damage as an end-point for normal tissue damage, ranged from 0.6 (without anaesthesia) to 1.6 (using nembutal as anaesthetic). The significantly elevated platinum levels in serum, kidney, jejunum and tumour tissue after WBH treatment may explain the thermal enhancement of DDP-mediated antitumour activity and side-effects but no correlation could be found for the differences in DDP-mediated normal tissue toxicities induced by the anaesthetics.
authors.affiliation: Department of Clinical Oncology, University Hospital Leiden, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Wondergem
authors.forename: Z H
authors.initials: ZH
authors.lastname: Siddik
authors.forename: F R
authors.initials: FR
authors.lastname: Strebel
authors.forename: J M
authors.initials: JM
authors.lastname: Bull
mesh_terms: D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005354:Fibrosarcoma / Q000737:chemistry / Q000628:therapy; D007036:Hypothermia, Induced; D010984:Platinum / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
chemical_list: D000777:Anesthetics; D010984:Platinum; D002945:Cisplatin