Avastin (bevacizumab)-induced tumor calcifications can be elicited in glioblastoma

[gdpawel]

J Intern Med. 2008 Sep;264(3):275-87.

Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood.

Weisenthal LM, Patel N, Rueff-Weisenthal C.

Weisenthal Cancer Group, Huntington Beach, CA 92647, USA. [email]mail@weisenthal.org

Abstract

BACKGROUND:

Angiogenesis studies are limited by the clinical relevance of laboratory model systems. We developed a new method for measuring dead microvascular (MV) cells in clinical tissue, fluid and blood specimens, and applied this system to make several potentially novel observations relating to cancer pharmacology.

METHODS:

Dead MV cells tend to have a hyperchromatic, refractile quality, further enhanced during the process of staining with Fast Green and counterstaining with either haematoxylin-eosin or Wright-Giemsa. We used this system to quantify the relative degree of direct antitumour versus anti-MV effects of cisplatin, erlotinib, imatinib, sorafenib, sunitinib, gefitinib and bevacizumab.

RESULTS:

Bevacizumab had striking anti-MV effects and minimal antitumour effects; cisplatin had striking antitumour effects and minimal anti-MV effects. The ;nib' drugs had mixed antitumour and anti-MV effects. Anti-MV effects of erlotinib and gefitinib were equal to those of sunitinib and sorafenib. There was no detectable VEGF in culture medium without cells; tumour cells secreted copious VEGF, reduced to undetectable levels by bevacizumab, greatly reduced by cytotoxic levels of cisplatin + anguidine, and variably reduced by DMSO and/or ethanol. We observed anti-MV additivity between bevacizumab and other drugs on an individual patient basis. Peripheral blood specimens had numerous MV cells which were strikingly visualized for quantification with public domain image analysis software using bevacizumab essentially as an imaging reagent.

CONCLUSIONS:

This system could be adapted for simple, inexpensive and sensitive/specific detection of tissue and circulating MV cells in a variety of neoplastic and non-neoplastic conditions, and for drug development and individualized cancer treatment.

PMID: 18793333 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/18793333

[gdpawel]

It's neither. It gives a much better understanding of what happens when Avastin is used. In pharmacology, the term agonist-antagonist is used to refer to a drug which exhibits some properties of an agonist (a substance that fully activates the neuronal receptor that it attaches to) and some properties of an antagonist (a substance that attaches to a receptor but does not activate it or if it displaces an agonist at that receptor it seemingly deactivates it thereby reversing the effect of the agonist).

When you culture endothelial cells with Avastin, all the VEGF gets pulled out of the culture medium and the endothelial cells undergo what is called "massive calcium accumulation death." Cytotoxic anticancer drugs antagonize the ability of Avastin to kill endothelial cells through this specific cell death mechanism. What is unique is that standard, traditional cytotoxic drugs inhibit Avastin, but the new "targeted" drugs don't inhibit it.

Clinical trials have shown that the combination of conventional chemotherapy with Avastin generally works better than either alone. 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. In other words, intermittent, "low dose" therapy might actually work much better than continuous "high dose" therapy.

In cell-based functional profiling assays, conducted on human tumor samples utilizing native microspheroids (fresh, live cells, not cell lines) replete with vascular, stromal and inflammatory cells to analyze cellular responses in the context of the tumor microenvironment, this snapshot of cellular response recapitulates patient response to cytotoxic compounds, signal transduction inhibitors and growth factor agonists/antagonists in real time.

Source: Cell Function Analysis