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 the rodent KHT sarcoma model either alone or in combination with radiation therapy. METHODS: KHT tumors were grown in C3H/HeJ mice. Combretastatin A-4 prodrug was injected intraperitoneally at doses ranging from 10 to 100 mg/kg. Tumors were irradiated in unanesthetized mice using a 137Cs source. Tumor response to combretastatin A-4 prodrug was assessed by histological evaluations as well as an in vivo to in vitro cell survival assay. RESULTS: Histological evaluation showed morphological damage of tumor cells within a few hours after drug treatment, followed by extensive central necrosis. Administering increasing doses of combretastatin A-4 prodrug to tumor-bearing mice resulted in a dose-dependent increase in cell killing irrespective of whether the tumors were irradiated or not. When combined with radiation, a 100 mg/kg dose of combretastatin A-4 prodrug reduced tumor cell survival 10-500-fold lower than that seen with radiation alone. Further, the shape of the cell survival curve observed following the combination therapy suggested that including combretastatin in the treatment had a major effect on the radiation-resistant hypoxic cell subpopulation associated with this tumor. CONCLUSION: The present results demonstrated that in the KHT sarcoma, combretastatin A-4 prodrug caused rapid vascular shutdown, a concentration-dependent direct cell killing, and effective enhancement of the antitumor effects of radiation therapy.[1]References
- Targeting the tumor vasculature with combretastatin A-4 disodium phosphate: effects on radiation therapy. Li, L., Rojiani, A., Siemann, D.W. Int. J. Radiat. Oncol. Biol. Phys. (1998) [Pubmed]
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