In vitro studies on interaction of 4-hydroperoxy-ifosfamide and radiotherapy in malignant gliomas

Drug-radiation multimodal chemotherapy for malignant brain tumor cells was stimulated in vitro by a recently developed computer program, based on evaluation of 3D-response surfaces and interaction isoboles. Three malignant glioma tumor cell cultures (HTZ17, 146 and 209 B) were sequentially treated in vitro by increasing doses of 4-hydroperoxy-ifosfamide, according to in vivo/in vitro pharmacokinetic correlation (0.01 to 10 microM), and increasing single doses of Gamma-radiation (clinical60Co-radiotherapy unit, 0.26 to 4 Gy or 1 to 3.38 Gy, respectively). After approximately five population doubling times with standard tissue culture conditions, 3H-Tdr-incorporation was determined by a liquid scintillation counting protocol. Data points were evaluated for mono- and combined treatment dose-effects. A model-free 3D-response surface was created and compared to the theoretical additive response surface. Local additivity was analysed for any desired ratio of combined treatment as well as for isoboles. No significant sub- or supraadditive effects were observed, indicating additive effects in all 3 tumors. No sequence dependence of effects could be demonstrated. In case radiotherapy and ifosfamide-chemotherapy are active treatment modalities and additive effects are found, we conclude that the combination of ifosfamide and radiotherapy might be attractive for the treatment of malignant brain tumors and should be further studied.