Optimisation of intraperitoneal cisplatin therapy with regional hyperthermia in rats

Gerrit Los, Peter Sminia, Jan Wondergem, Peter H.A. Mutsaers, Jaap Havemen, Daan ten Bokkel Huinink, Oskar Smals, Dionisio Gonzalez-Gonzalez, J. Gordon McVie

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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°C (factor 4) and 43°C (factor 6) compared to 37°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°C, 1 h). The mean (S.D.) temperature in the peritoneal cavity was 41.5 (0.3)°C and outside the peritoneal cavity 40.5 (0.3)°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 μmol/l/min to 486 μmol/l/min at 37°C and 41.5°C, respectively), and for total and ultrafiltered platinum in the blood. The AUC for total platinum increased from 97.9 to 325.8 μmol/min and for ultrafiltered platinum from 22.2 to 107 μmol/l/min at 37°C and 41.5°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.

Original languageEnglish
Pages (from-to)472-477
Number of pages6
JournalEuropean Journal of Cancer and Clinical Oncology
Volume27
Issue number4
DOIs
Publication statusPublished - 1 Jan 1991

Cite this

Los, G., Sminia, P., Wondergem, J., Mutsaers, P. H. A., Havemen, J., ten Bokkel Huinink, D., ... Gordon McVie, J. (1991). Optimisation of intraperitoneal cisplatin therapy with regional hyperthermia in rats. European Journal of Cancer and Clinical Oncology, 27(4), 472-477. https://doi.org/10.1016/0277-5379(91)90389-U
Los, Gerrit ; Sminia, Peter ; Wondergem, Jan ; Mutsaers, Peter H.A. ; Havemen, Jaap ; ten Bokkel Huinink, Daan ; Smals, Oskar ; Gonzalez-Gonzalez, Dionisio ; Gordon McVie, J. / Optimisation of intraperitoneal cisplatin therapy with regional hyperthermia in rats. In: European Journal of Cancer and Clinical Oncology. 1991 ; Vol. 27, No. 4. pp. 472-477.
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abstract = "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°C (factor 4) and 43°C (factor 6) compared to 37°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°C, 1 h). The mean (S.D.) temperature in the peritoneal cavity was 41.5 (0.3)°C and outside the peritoneal cavity 40.5 (0.3)°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 μmol/l/min to 486 μmol/l/min at 37°C and 41.5°C, respectively), and for total and ultrafiltered platinum in the blood. The AUC for total platinum increased from 97.9 to 325.8 μmol/min and for ultrafiltered platinum from 22.2 to 107 μmol/l/min at 37°C and 41.5°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.",
author = "Gerrit Los and Peter Sminia and Jan Wondergem and Mutsaers, {Peter H.A.} and Jaap Havemen and {ten Bokkel Huinink}, Daan and Oskar Smals and Dionisio Gonzalez-Gonzalez and {Gordon McVie}, J.",
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Los, G, Sminia, P, Wondergem, J, Mutsaers, PHA, Havemen, J, ten Bokkel Huinink, D, Smals, O, Gonzalez-Gonzalez, D & Gordon McVie, J 1991, 'Optimisation of intraperitoneal cisplatin therapy with regional hyperthermia in rats' European Journal of Cancer and Clinical Oncology, vol. 27, no. 4, pp. 472-477. https://doi.org/10.1016/0277-5379(91)90389-U

Optimisation of intraperitoneal cisplatin therapy with regional hyperthermia in rats. / Los, Gerrit; Sminia, Peter; Wondergem, Jan; Mutsaers, Peter H.A.; Havemen, Jaap; ten Bokkel Huinink, Daan; Smals, Oskar; Gonzalez-Gonzalez, Dionisio; Gordon McVie, J.

In: European Journal of Cancer and Clinical Oncology, Vol. 27, No. 4, 01.01.1991, p. 472-477.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Optimisation of intraperitoneal cisplatin therapy with regional hyperthermia in rats

AU - Los, Gerrit

AU - Sminia, Peter

AU - Wondergem, Jan

AU - Mutsaers, Peter H.A.

AU - Havemen, Jaap

AU - ten Bokkel Huinink, Daan

AU - Smals, Oskar

AU - Gonzalez-Gonzalez, Dionisio

AU - Gordon McVie, J.

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Y1 - 1991/1/1

N2 - 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°C (factor 4) and 43°C (factor 6) compared to 37°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°C, 1 h). The mean (S.D.) temperature in the peritoneal cavity was 41.5 (0.3)°C and outside the peritoneal cavity 40.5 (0.3)°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 μmol/l/min to 486 μmol/l/min at 37°C and 41.5°C, respectively), and for total and ultrafiltered platinum in the blood. The AUC for total platinum increased from 97.9 to 325.8 μmol/min and for ultrafiltered platinum from 22.2 to 107 μmol/l/min at 37°C and 41.5°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.

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