Recombinant human vascular endothelial growth factor (rhVEGF165b) as a therapeutic dose for heterotopic human colon cancer in mice


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Gopinath Damodaran, Sandeep Dyayade, Steven J Harper, David O Bates

University of Bristol, UK

Abstract

Background

Angiogenesis is stimulated by vascular endothelial growth factor (VEGF). Anti-VEGF therapy, such as Avastin, is a novel therapeutic approach to the treatment of cancer, but tumours have shown resistance to antibody-based therapies. Alternative splicing into the terminal exon 8 give rise to two families of isoforms, VEGFxxxb and VEGFxxx. The endogeneous splice variant VEGF165b, binds VEGF receptor 2 with same affinity as VEGF165 and thus acts as anti-angiogenic factor. VEGF165b may be a useful tool in suppressing tumour growth by blocking angiogenesis.

Method

In this study the therapeutic dose of intravenous injection of rhVEGF165b was studied on LS174t (colonic carcinoma cells) in a mouse xenograft model and compared with Avastin. LS174t cells were injected subcutaneously into nude mice. Tumour bearing mice (> 3mm) were treated by bi-weekly tail vein injection of 100g rhVEGF165b protein, or intraperitoneal injection of 50g Avastin, or saline. The tumour size was measured tri-weekly and tumour volumes were compared by one way analysis of variance followed by post hoc test.

Results

Recombinant VEGF165b significantly inhibited the growth of tumours, and was equivalent to Avastin injection (p<0.001). Pharmacokinetic and tissue uptake of rhVEGF165b at different time intervals (4,8,12,24 and 48h) was quantified. Therapeutic dose of rhVEGF165b showed a half-life of 1.5h.

Conclusion

These results indicate that the therapeutic dose of rhVEGF165b was taken up into the tumour, suppressed tumour growth, indicating that it may be an effective tool in controlling colon cancer progression. Supported by Philogene Inc.