Endothelial Massive Calcium Accumulation Death (MCAD): Mechanism, Target, and Predictive Biomarker for Anti-Angiogenic Therapy.
13th international symposium on anti-angiogenic therapy: recent advances and future directions in basic and clinical cancer research. LaJolla, CA. February 2011
When you culture endothelial cells (either pure cultures of endothelial cells or endothelial cells associated with fresh human tumor microclusters) with Avastin, all of the VEGF gets pulled out of the culture medium and the endothelial cells undergo what is called "massive calcium accumulation death."
Cytotoxic anticancer drugs (topotecan, vinorelbine, melphalan, doxorubicin, cisplatin) antagonize the ability of Avastin to kill endothelial cells through this specific cell death mechanism. The standard, traditional cytotoxic drugs all inhibited Avastin, but the new, "targeted" drugs either don't inhibit it or actually enhance it (e.g. lapatinib, erlotinib).
Clinical trials have shown that the combination of chemotherapy with Avastin generally works better than either alone (that is, in situations where Avastin works at all). But this is because Avastin has a very long half life (weeks) and it has the opportunity to work at times when the drug levels of the standard anticancer drugs go down to undetectable levels (where they won't antagonize the ability of low VEGF to cause death of the tumor endothelial cells).
It would be predictive that continuous chemotherapy with a drug like Taxol would be antagonistic; so that intermittent, lower dose therapy might actually work much better than continuous high dose therapy. This is a theoretical extrapolation from cell culture data.
The mechanism of antagonism is that the "MCAD" (massive calcium accumulation death of endothelial cells) is a bioenergetically active process. I'm sure that there's a specific pathway for it that someone will eventually work out and that non-specific cytotoxins inhibit this active process and, thus, the withdrawal of VEGF can't trigger this active, MCAD form of endothelial cell death.
Bibliography relevant to AngioRx/Microvascular Viability assay (MVVA)
1. Weisenthal, L. M. Patel, N., Rueff-Weisenthal, C. (2008). "Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood." J Intern Med 264(3): 275-287.
2. Weisenthal, L., Lee, DJ, and Patel, N. (2008). Antivascular activity of lapatinib and bevacizumab in primary microcluster cultures of breast cancer and other human neoplasms. ASCO 2008 Breast Cancer Symposium. Washington, D.C.: Abstract # 166. Slide presentation at: http://tinyurl.com/weisenthal-breast-lapatinib
3. Weisenthal, L. M. (2010). Antitumor and anti-microvascular effects of sorafenib in fresh human tumor culture in comparison with other putative tyrosine kinase inhibitors. J Clin Oncol 28, 2010 (suppl; abstr e13617)
4.Weisenthal, L., H. Liu, Rueff-Weisenthal, C. (2010). "Death of human tumor endothelial cells in vitro through a probable calcium-associated mechanism induced by bevacizumab and detected via a novel method." Nature Precedings 28 May 2010. from http://hdl.handle.net/10101/npre.2010.4499.1
5. Weisenthal, Larry. Endothelial Massive Calcium Accumulation Death (MCAD): Mechanism, Target, and Predictive Biomarker for Anti-Angiogenic Therapy. 13th international symposium on anti-angiogenic therapy: recent advances and future directions in basic and clinical cancer research. LaJolla, CA. February 2011
Available from Nature Precedings http://dx.doi.org/10.1038/npre.2011.6647.1
6. Weisenthal, L, Williamson, S, Ryan, K, Brunshwiler, C, and Rueff-Weisenthal, C. Massive calcium uptake in human endothelial cells, submitted for publication.
7.Bevacizumab-induced tumor calciﬁcations can be elicited in glioblastoma microspheroid culture and represent massive calcium uptake death (MCAD) of tumor endothelial cells. Larry Weisenthal, Summer Williamson, Cindy Brunschwiler, and Constance Rueff-Weisenthal, 14th International Anti-Angiogenesis Symposium, LaJolla CA, Feb 2012. Available from Nature Precedings http://dx.doi.org/10.1038/npre.2012.7069.1