Vascular effects dominate solid tumor response to treatment with combretastatin A-4-phosphate.

Vascular-targeted therapeutics are increasingly used in the clinic. However, less is known about the direct response of tumor cells to these agents. We have developed a combretastatin-A-4-phosphate (CA4P) resistant variant of SW1222 human colorectal carcinoma cells to examine the relative importance of vascular versus tumor cell targeting in the ultimate treatment response. SW1222^Res cells were generated through exposure of wild-type cells (SW1222^WT) to increasing CA4P concentrations in vitro. Increased resistance was confirmed through analyses of cell viability, apoptosis and multidrug-resistance (MDR) protein expression. In vivo, comparative studies examined tumor cell necrosis, apoptosis, vessel morphology and functional vascular end-points following treatment with CA4P (single 100 mg/kg dose). Tumor response to repeated CA4P dosing (50 mg/kg/day, 5 days/week for 2 weeks) was examined through growth measurement, and ultimate tumor cell survival was studied by ex vivo clonogenic assay. In vitro, SW1222^Res cells showed reduced CA4P sensitivity, enhanced MDR protein expression and a reduced apoptotic index. In vivo, CA4P induced significantly lower apoptotic cell death in SW1222^Res versus SW1222^WT tumors indicating maintenance of resistance characteristics. However, CA4P-induced tumor necrosis was equivalent in both lines. Similarly, rapid CA4P-mediated vessel disruption and blood flow shut-down were observed in both lines. Cell surviving fraction was comparable in the two tumor types following single dose CA4P and SW1222^Res tumors were at least as sensitive as SW1222^WT tumors to repeated dosing. Despite tumor cell resistance to CA4P, SW1222^Res response in vivo was not impaired, strongly supporting the view that vascular damage dominates the therapeutic response to this agent. [ABSTRACT FROM AUTHOR]