TARGETING THE TUMOR VASCULATURE WITH COMBRETASTATIN A-4 DISODIUM PHOSPHATE - EFFECTS ON RADIATION-THERAPY

Purpose: The aim of this study was to evaluate the antitumor efficacy of combretastatin A-4 disodium phosphate (combretastatin prodrug) in t he rodent KHT sarcoma model either alone or in combination with radiat ion therapy. Methods: KHT tumors were grown in C3H/HeJ mice, Combretas tatin A-4 prodrug was injected intraperitoneally at doses ranging from 10 to 100 mg/kg, Tumors were irradiated in unanesthetized mice using a Cs-137 source, Tumor response to combretastatin A-4 prodrug was asse ssed by histological evaluations as well as an in vivo to in vitro cel l survival assay. Results: Histological evaluation showed morphologica l damage of tumor cells within a few hours after drug treatment, follo wed by extensive central necrosis, Administering increasing doses of c ombretastatin A-4 prodrug to tumor-bearing mice resulted in a dose-dep endent increase in cell killing irrespective of whether the tumors wer e irradiated or not. When combined with radiation, a 100 mg/kg dose of combretastatin A-4 prodrug reduced tumor cell survival 10-500-fold lo wer than that seen with radiation alone. Further, the shape of the cel l survival curve observed following the combination therapy suggested that including combretastatin in the treatment had a major effect on t he radiation-resistant hypoxic cell subpopulation associated with this tumor. Conclusion: The present results demonstrated that in the KHT s arcoma, combretastatin A-4 prodrug caused rapid vascular shutdown, a c oncentration-dependent direct cell killing, and effective enhancement of the antitumor effects of radiation therapy. (C) 1998 Elsevier Scien ce Inc.