The vascular disrupting agent ZD6126 shows increased antitumor efficacy and enhanced radiation response in large, advanced tumors.
OBJECTIVE
ZD6126 is a vascular-targeting agent that induces selective effects on the morphology of proliferating and immature endothelial cells by disrupting the tubulin cytoskeleton. The efficacy of ZD6126 was investigated in large vs. small tumors in a variety of animal models.


METHODS
Three rodent tumor models (KHT, SCCVII, RIF-1) and three human tumor xenografts (Caki-1, KSY-1, SKBR3) were used. Mice bearing leg tumors ranging in size from 0.1-2.0 g were injected intraperitoneally with a single 150 mg/kg dose of ZD6126. The response was assessed by morphologic and morphometric means as well as an in vivo to in vitro clonogenic cell survival assay. To examine the impact of tumor size on the extent of enhancement of radiation efficacy by ZD6126, KHT sarcomas of three different sizes were irradiated locally with a range of radiation doses, and cell survival was determined.


RESULTS
All rodent tumors and human tumor xenografts evaluated showed a strong correlation between increasing tumor size and treatment effect as determined by clonogenic cell survival. Detailed evaluation of KHT sarcomas treated with ZD6126 showed a reduction in patent tumor blood vessels that was approximately 20% in small (<0.3 g) vs. >90% in large (>1.0 g) tumors. Histologic assessment revealed that the extent of tumor necrosis after ZD6126 treatment, although minimal in small KHT sarcomas, became more extensive with increasing tumor size. Clonogenic cell survival after ZD6126 exposure showed a decrease in tumor surviving fraction from approximately 3 x 10(-1) to 1 x 10(-4) with increasing tumor size. When combined with radiotherapy, ZD6126 treatment resulted in little enhancement of the antitumor effect of radiation in small (<0.3 g) tumors but marked increases in cell kill in tumors larger than 1.0 g.


CONCLUSIONS
Because bulky neoplastic disease is typically the most difficult to manage, the present findings provide further support for the continued development of vascular disrupting agents such as ZD6126 as a vascular-targeted approach to cancer therapy.
Siemann
Dietmar W
DW
Department of Radiation Oncology, University of Florida Shands Cancer Center, Gainesville, FL 32610, USA. siemadw@ufl.edu
Rojiani
Amyn M
AM
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles; D004354:Drug Screening Assays, Antitumor; D005456:Fluorescent Dyes; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009336:Necrosis; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D012509:Sarcoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D014183:Transplantation, Heterologous
D020533:Angiogenesis Inhibitors; D001562:Benzimidazoles; D005456:Fluorescent Dyes; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; C017807:bisbenzimide ethoxide trihydrochloride