Effect of the second-generation vascular disrupting agent OXi4503 on tumor vascularity.
OBJECTIVE
As first-generation small-molecule vascular disrupting agents (VDA) have begun to enter clinical trials, second-generation agents are under active development. One such agent is the combretastatin A4 disodium phosphate (CA4P) analogue OXi4503 (CA1P).


METHODS
C3H/HeJ mice bearing KHT sarcomas were treated with CA4P and OXi4503 and the effect on tumor vasculature was determined by evaluating the extent of vascular shutdown (Hoechst-33342 vessel staining) and tumor perfusion inhibition (dynamic contrast-enhanced magnetic resonance imaging). Dynamic contrast-enhanced magnetic resonance imaging and tumor necrosis end points also were used to examine the pathophysiologic tumor effects following repeated exposures to these agents.


RESULTS
Single doses of either agent (CA4P, 100 mg/kg; OXi4503, 25 mg/kg) resulted in an 80% to 90% reduction in tumor perfusion 4 hours after treatment. Whereas recovery in tumor perfusion was observed 48 hours posttreatment, this recovery was significantly slower in mice treated with OXi4503. Tumors re-treated with either VDA 72 hours after the first drug exposure showed a similar reduction and recovery in tumor perfusion. Histologic evidence showed the presence of a smaller viable rim after exposure to OXi4503 than that observed after CA4P treatment. Furthermore, the extent of recovery of tumor necrosis 72 hours after drug treatment was less for OXi4053.


CONCLUSIONS
The present studies show that the second-generation VDA OXi4503 possesses significant antivascular effects in solid tumors. Importantly, the vasculature of tumors of mice that had received an initial dose this agent was as responsive to a subsequent treatment.
Salmon
Howard W
HW
Department of Radiation Oncology, Shands Cancer Center, University of Florida, Gainesville, Florida 32610, USA. hwsalmon@ufl.edu
Siemann
Dietmar W
DW
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D011756:Diphosphates / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D007274:Injections, Intraperitoneal; D008279:Magnetic Resonance Imaging; D051379:Mice; D008809:Mice, Inbred C3H; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D011859:Radiography; D012513:Sarcoma, Experimental / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy*; D013267:Stilbenes / Q000008:administration & dosage*; D013997:Time Factors; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D011756:Diphosphates; C465018:Oxi 4503; D013267:Stilbenes; C058728:fosbretabulin