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Interaction between combretastatin A-4 disodium phosphate and radiation in murine tumors
R Murata1, D W Siemann, J Overgaard
1Danish Cancer Society, Department of Experimental Clinical Oncology, Aarhus University Hospital, Nørrebrogade 44, Building 5, DK-8000 C, Aarhus, Denmark.
Background And Purpose:
The ability of combretastatin A-4 disodium phosphate (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 foot 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 intraperitoneally. Tumor blood perfusion was estimated using 86RbCl extraction and Hoechst 33342 fluorescent labelling. Necrotic fraction was determined from histological sections. Tumors were locally irradiated in non-anaesthetised mice and response assessed by local tumor control for the C3H mammary carcinoma 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 250 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 carcinoma the enhancement was only significant when administered at the same time or after the radiation, with no enhancement seen if CA4DP was given before. These effects were drug-dose dependent. CA4DP did not enhance radiation damage in normal skin.
Conclusions:
CA4DP enhanced radiation damage in the two tumor models without enhancing normal tissue damage. These radiation effects were clearly consistent with the anti-vascular action of CA4DP.
