VEGF-associated tyrosine kinase inhibition increases the tumor response to single and fractionated dose radiotherapy

Purpose: In this study, the efficacy of combining ZD6474 (Zactima), a vascular endothelial growth factor (VEGF) receptor 2-associated tyrosine kinase inhibitor currently undergoing Phase II clinical trial evaluation, with single and fractionated dose radiation exposures was examined in a human colorectal carcinoma model (HT29). Methods and Materials: HT29 xenograft-bearing mice were treated with either single-dose (10 Gy) or multifraction (2 Gy/day for 2 weeks) radiotherapy alone or in conjunction with a 2-week course of ZD6474 (25 mg/kg). In the single-dose investigation, ZD6474 treatment followed radiotherapy, whereas in the fractionated dose studies the antiangiogenic therapy was given before, after, or concurrent with the radiation. Tumor response was determined by tumor growth delay. Results: ZD6474 increased the response of HT29 xenografts to both single and fractionated dose radiotherapy. In the fractionation studies sequencing of therapies had little impact on treatment outcomes; the time for the median tumors in each of the treatment groups to grow to five times the starting size was 53, 53.5, and 49 days, respectively. Conclusions: These studies indicate that ZD6474, when used in conjunction with radiation therapy, has a clear therapeutic advantage, providing a rationale for considering the combination of this agent with radiotherapy in the clinic. (c) 2006 Elsevier Inc.