Combretastatin A-4 disodium phosphate: A vascular targeting agent that improves the anti-tumor effects of hyperthermia, radiation, and mild thermoradiotherapy

Purpose: To investigate the effect of combining the vascular targeting drug combretastatin A-4 disodium phosphate (CA4DP) with hyperthermia, radiation , or mild thermoradiotherapy in a transplanted C3H mouse mammary carcinoma. Methods and Materials: The C3H mammary carcinoma was grown on the rear foot of female CDF1 mice and treated when at 200 mm(3) in size. CA4DP was disso lved in saline and injected i.p. Hyperthermia and/or radiation were locally given to tumors in restrained nonanesthetized mice. Tumor response was ass essed using either a tumor growth or a tumor control assay. Mouse foot skin was used to assess normal tissue damage. Results: CA4DP significantly enhanced thermal damage in this tumor model. T his effect was independent of drug doses between 25-400 mg/kg, but was stro ngly dependent on the time interval between drug injection and heating, wit h the greatest improvement seen when CA4DP preceded the heating by I h or l ess. There was also a suggestion of a temperature dependency with a 1.9-fol d increase in heat damage at 42.5 degreesC and a 2.6-fold increase at 41.5 and 40.5 degreesC. Heat-induced normal tissue damage was also enhanced by c ombining CA4DP with heat, but the degree of enhancement was less than that seen in tumors. CA4DP (25 mg/kg) significantly increased radiation-induced local tumor control and this was further enhanced by combining CA4DP with m ild temperature (41.5 degreesC, 60 min) heating. Conclusions: CA4DP improved the anti-tumor effect of hyperthermia, especial ly at mild temperatures. More importantly, it also increased the tumor resp onse to mild hyperthermia and radiation, which suggests that CA4DP may ulti mately have an important application in clinical thermoradiotherapy. (C) 20 01 Elsevier Science Inc.