Purpose-The purpose of this study was to examine the pathophysiologic impact of CA4P treatment in regions of tumors that ultimately either necrose or survive treatment with such agents.Methods and Materials-Proliferation, perfusion, vessel density, and VEGF expression were analyzed in the KHT tumor model following CA4P treatment. Analyses were conducted in the whole tumor and the tumor periphery.Results-Perfusion in the tumor periphery decreased 4 hours after treatment but returned to baseline 20 hours later. Whole tumor perfusion also decreased 4 hours after treatment, but did not return to baseline. Vessel density decreased in the tumor as a whole, but not in the tumor periphery. No significant effect on VEGF expression was observed, but a decrease in proliferation in the whole tumor and the periphery was noted.Conclusions-The present studies have shown that those areas of the tumor that survive CA4P treatment are affected by CA4P exposure, though only transiently. The decrease in perfusion could negatively impact therapies utilizing the combination of CA4P and conventional anticancer agents by decreasing drug delivery and tissue oxygenation.These findings suggest that the timing of CA4P treatments when used in conjunction with conventional anticancer therapies should be considered carefully.

The purpose of this study was to investigate two non-invasive methods for determining the treatment efficacy of the vascular disrupting agent (VDA) CA4P: gadolinium enhanced dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for perfusion analysis and enzyme-linked immunosorbent assay (ELISA) of blood samples. Candidate proteins were identified by multi-analyte profile analysis of plasma from KHT sarcoma-bearing C3H/HeJ mice after CA4P administration. Candidate proteins were further analysed by ELISA of plasma from treated C3H/HeJ, BALBc and C57BL6 mice. Changes in selected proteins, tumour perfusion and tumour necrotic fraction after CA4P treatment were then compared in individual animals. The cytokines KC and MCP-1 were observed to increase after CA4P treatment in all tested models. No correlation was found between KC or MCP-1 levels and tumour necrosis. However, tumour perfusion correlated (r=0.89, p<0.00001) with CA4P treatment efficacy as measured by necrotic fraction, suggesting that DCE-MRI may have utility in a clinical setting.

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