IN-VITRO STUDIES ON INTERACTION OF 4-HYDROPEROXY-IFOSFAMIDE AND RADIOTHERAPY IN MALIGNANT GLIOMAS

Drug-radiation multimodal chemotherapy for malignant brain tumor cells was simulated in vitro by a recently developed computer program, base d on evaluation of 3D-response surfaces and interaction isoboles. Thre e malignant glioma tumor cell cultures (HTZ 17, 146 and 209 B) were se quentially treated in vitro by increasing doses of I-hydroperoxy-ifosf amide, according to in vivo/in vitro pharmacokinetic correlation (0.01 to 10 mu M), and increasing single doses of Gamma-radiation (clinical Co-60-radiotherapy unit, 0.26 to 4 Gy or 1 to 3.38 Gy, respectively). After approximately five population doubling times with standard tiss ue culture conditions, H-3-Tdr-incorporation was determined by a liqui d scintillation counting protocol. Data points were evaluated for mono - and combined treatment dose-effects. A model-free 3D-response surfac e was created and compared to the theoretical additive response surfac e. Local additivity was analysed for any desired ratio of combined tre atment as well as for isoboles. No significant sub- or supraadditive e ffects were observed, indicating additive effects in all 3 tumors. No sequence dependence of effects could be demonstrated. In case radiothe rapy and ifosfamide-chemotherapy are active treatment modalities and a dditive effects are found, we conclude that the combination of ifosfam ide and radiotherapy might be attractive for the treatment of malignan t brain tumors and should be further studied.