Optimisation of intraperitoneal cisplatin therapy with regional hyperthermia in rats.
The purpose of this study was to optimise intraperitoneal chemotherapy by combining this modality with regional hyperthermia. In vitro data demonstrated that both the uptake of cisplatin into CC531 tumour cells and cytotoxicity were increased at temperatures of 40 degrees C (factor 4) and 43 degrees C (factor 6) compared to 37 degrees C. The increase of intracellular platinum concentration correlated well with the decrease in survival of these cells. In vivo, rats were treated intraperitoneally with cisplatin (5 mg/kg) in combination with regional hyperthermia of the abdomen (41.5 degrees C, 1 h). The mean (S.D.) temperature in the peritoneal cavity was 41.5 (0.3) degrees C and outside the peritoneal cavity 40.5 (0.3) degrees C. Enhanced platinum concentrations were found in peritoneal tumours (factor 4.1) and kidney, liver, spleen and lung (all around a factor 2.0), after combined cisplatin-hyperthermia treatment. The platinum distribution in peritoneal tumours was more homogeneous after the combined treatment than after cisplatin alone, possibly due to increased penetration of cisplatin into peritoneal tumours. Pharmacokinetic data demonstrated an increased tumour exposure for unfiltered platinum in the peritoneal cavity (area under the curve [AUC] increased from 339 mumol/l/min to 486 mumol/l/min at 37 degrees C and 41.5 degrees C, respectively), and for total and ultrafiltered platinum in the blood. The AUC for total platinum increased from 97.9 to 325.8 mumol/min and for ultrafiltered platinum from 22.2 to 107 mumol/l/min at 37 degrees C and 41.5 degrees C respectively. The latter might be due to a slower elimination of platinum from the blood. The combined treatment, intraperitoneal cisplatin and regional hyperthermia, also increased toxicity. The thermal enhancement ratio (TER) using lethality as endpoint was 1.8.
Los
G
G
The Netherlands Cancer Institute, Division of Experimental Chemotherapy, Amsterdam.
Sminia
P
P
Wondergem
J
J
Mutsaers
P H
PH
Havemen
J
J
ten Bokkel Huinink
D
D
Smals
O
O
Gonzalez-Gonzalez
D
D
McVie
J G
JG
D000818:Animals; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D006979:Hyperthermia, Induced / Q000009:adverse effects; D008297:Male; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010534:Peritoneal Neoplasms / Q000378:metabolism*; D010984:Platinum / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013696:Temperature; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000187:drug effects
D010984:Platinum; D002945:Cisplatin