Bevacizumab/docetaxel association is more efficient than docetaxel alone in reducing breast and prostate cancer cell growth: A new paradigm for understanding the therapeutic effect of combined treatment

Bevacizumab (Bvz) a Vascular Endothelial Growth Factor (VEGF) targeted humanised monoclonal antibody provides clinical benefit in combination with docetaxel (DXL) a microtubule stabilising agent in the treatment of metastatic breast and prostate cancers Since VEGF and their receptors are expressed by tumour cells we hypothesised that Bvz in addition to its impact on neo vascularisation could have an impact on tumour cells and enhance the DXL activity Hence we studied the effect of DXL and Bvz on metastatic breast (MDA MB 231) and prostate (PC3) cancer cells lines Bvz alone did not decrease cell proliferation but in combination with DXL Bvz enhanced the anti proliferative activity of DXL Other anti angiogenic factors Sunitinib Sorafenib and Gefitinib enhanced the anti prolifer ative effect of DXL qPCR experiments showed that DXL significantly increased the VEGF and VEGF receptor 2 (VEGF R2) mRNA levels Activation of VEGF and VEGF R2 promoters demonstrated that enhanced mRNA levels are partly due to transcriptional activation ELISA assays showed that DXL induced accumulation of cytoplasmic VEGF but decreased extracellular levels by 39% (MDA) and 48% (PC3) Cell surface localisation of VEGF R2 was increased by DXL alone but decreased after combined treatment of DXL plus Bvz Abnormal expression of VEGF R2 was also shown on breast and prostate tumour samples rein forcing the results obtained on cellular models In conclusion DXL and Bvz in combination decreased extracellular VEGF and VEGF R2 levels at the plasma membrane thereby blocking an important growth/survival loop Thus the combined therapeutic impact of Bvz and DXL observed in clinical trials is associated with enhanced anti prolifer ative activity and inhibition of the vascular network (c) 2010 Elsevier Ltd All rights reserved