Effects of ASA404, a vascular disrupting agent, on tumor growth of gastric cancer in an experimental model.

Abstract

48 Background: A functional vascular system is essential for growth of solid malignancies including gastric cancer. For establishment and maintenance of such a vascular system endothelial cells (ECs) and pericytes (e.g. vascular smooth muscle cells, VSMC) are required. We hypothesized that targeting tumor vasculature with the vascular disrupting agent (VDA) ASA404 (Novartis Oncology) reduces tumor growth in a model of gastric cancer. Methods: Gastric cancer (GC) cell lines, ECs and VSMCs were used for experiments. Effects of ASA404 on growth of GC, EC and VSMC were assessed by MTT assays. Impact of ASA404 (20 mg/kg on day 1, 5, 9) in combination with paclitaxel (10 mg/kg on day 1 and 7) on tumor growth was assessed in a subcutaneous tumor model. Treatment was started when tumors reached a size of approximately 200 mm3. Tumors were measured and harvested on day 23 for IHC analyses. Effect of ASA404 on blood perfusion of tumors during therapy was monitored by contrast-enhanced ultrasound (CEUS). Results: In vitro ASA404 impaired growth of ECs and VSMCs upon stimulation with condition media from gastric cancer cells. No direct effect on tumor cells was observed. In vivo, treatment with ASA404 led to marked decrease of tumor perfusion and an increase of necrosis as determined by CEUS. Furthermore, combination of ASA404 with paclitaxel showed significant reduction of tumor growth compared to controls (p < 0.05). In addition, tumor vascularisation and tumor cell proliferation were significantly reduced as determined by CD31-positive vessel area and BrdU-positive cells (p < 0.05). Conclusions: Combination of the VDA ASA404 with paclitaxel impairs tumor growth and perfusion of gastric cancer in an experimental model. Hence, targeting tumor vasculature with ASA404 appears to be a promising strategy for therapy of gastric cancer. No significant financial relationships to disclose.