Interaction between combretastatin A-4 disodium phosphate and radiation inmurine tumors

Background anti purpose: The ability of combretastatin A-4 disodium phospha te (CA4DP) to induce vascular damage and enhance the radiation response of murine tumors was investigated. Materials and methods: A C3H mouse mammary carcinoma transplanted in the fo ot of CDF1 mice and the KHT mouse sarcoma growing in the leg muscle of C3H/ HeJ mice were used. CA4DP was dissolved in saline and injected intraperiton eally. Tumor blood perfusion was estimated using (RbCl)-Rb-86 extraction an d Hoechst 33342 fluorescent labelling. Necrotic fraction was determined fro m histological sections. Tumors were locally irradiated in non-anaesthetise d mice and response assessed by local tumor control for the C3H mammary car cinoma and in vivo/in vitro clonogenic cell survival for the KHT sarcoma. Results: CA4DP decreased tumor blood perfusion and increased necrosis in a dose-dependent fashion in the C3H mammary carcinoma, which was maximal at 2 50 mg/kg. The decrease in perfusion and induction of necrosis by CA4DP was more extensive in the KHT sarcoma. CA4DP enhanced radiation damage in both tumor types. In the KHT sarcoma this enhancement was independent of whether the drug was given before or after irradiating, whereas for C3H mammary ca rcinoma the enhancement was only significant when administered at the same time or after the radiation, with no enhancement seen if CA4DP was given be fore. These effects were drug-dose dependent. CA4DP did not enhance radiati on damage in normal skin. Conclusions: CA4DP enhanced radiation damage in the two tumor models withou t enhancing normal tissue damage. These radiation effects were clearly cons istent with the anti-vascular action of CA4DP. (C) 2001 Elsevier Science Ir eland Ltd. All rights reserved.