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| Item type: | Article | ||||||||||||||||
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| Journal or Publication Title: | Journal of cancer research and clinical oncology | ||||||||||||||||
| Publisher: | Springer | ||||||||||||||||
| Volume: | 117 | ||||||||||||||||
| Number of Issue or Book Chapter: | Suppl | ||||||||||||||||
| Page Range: | S157-163 | ||||||||||||||||
| Date: | 1991 | ||||||||||||||||
| Institutions: | Medicine > Zentren des Universitätsklinikums Regensburg > Zentrum für Hirntumore (ZHT) | ||||||||||||||||
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| Classification: |
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| Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine | ||||||||||||||||
| Status: | Published | ||||||||||||||||
| Refereed: | Yes, this version has been refereed | ||||||||||||||||
| Created at the University of Regensburg: | Unknown | ||||||||||||||||
| Item ID: | 29390 |
Abstract
Combination chemotherapy is widely employed in clinical oncology; however, there is no generally accepted model to evaluate individual tumour susceptibility to a given drug combination protocol. We therefore investigated the drug interaction of ifosfamide (4-hydroxyperoxy-ifosfamide) and ACNU in a recently developed in vitro model of paired sequential combination chemotherapy in primary and ...
Abstract
Combination chemotherapy is widely employed in clinical oncology; however, there is no generally accepted model to evaluate individual tumour susceptibility to a given drug combination protocol. We therefore investigated the drug interaction of ifosfamide (4-hydroxyperoxy-ifosfamide) and ACNU in a recently developed in vitro model of paired sequential combination chemotherapy in primary and metastatic malignant brain tumours. A long-term standard [6,3-3H]-thymidine-incorporation assay, employing a liquid scintillation counting protocol, was selected to assess the drug sensitivity of human tumours. In vitro drug exposures were derived from correlating in vivo-(systemic and CNS) and in vitro-pharmacokinetic drug parameters. In combination experiments tumour cells were treated sequentially by two drugs in both sequences: drug exposures were calculated for 2 h with a 1-h drug-free interval in between. "Cut-off" concentrations (maximum in vitro exposure doses) were calculated as 1.74 microM (for primary CNS tumours: 0.58 microM) for ifosfamide and 5.4 microM (for primary CNS tumours: 1.33 microM) for ACNU. Dose/response relations were derived from isotope incorporation rates after cells had grown for approximately five population doubling times. Combination isoboles were plotted after drug doses had been transformed into "equieffective doses", enabling comparison of drug combination effects. In all three glioblastomas (with CNS exposure dose) an additive or supra-additive effect could be observed in either sequence (in one tumour a biphasic additive isobole was found for both sequences). Out of three bronchial carcinomas (small-cell type, brain metastases) in two non-identical sequences a supra-additive effect was observed in two tumours, with antagonistic effects in the third tumour. In all three malignant melanomas and in one renal carcinoma antagonistic effects were observed, whereas in a second renal carcinoma supra-additive effects were demonstrated for both sequences. We conclude that drug combination chemotherapy effects at the cellular level may be extremely heterogeneous.
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