[gdpawel]

Dr. Robert Nagourney blogged some interesting insight into this. What is the appropriate dose of Avastin? How should it be given? In what sequence with radiation or chemotherapy? With what drugs or targeted agents? Are low doses better than high doses? Is the effect of VGEF inhibition a driver of response or an epiphenomenon? What about the fibroblast matrix, lymphatic vessels, infiltrating monocytes, T-cells, B-cells and neutrophils?

[url]http://robertanagourney.wordpress.com/2012/06/08/tumor-ecology-not-tumor-biology/

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).

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.

Tamoxifen acts as an antagonist in breast and conversely an agonist in uterus. Agonist (potentiating) effects at high doses. Sometimes agents can "chemosensitize" tumor cells. To alter susceptibility of a targeted cell or organism having become ineffective, becomes effective again. There is a chemosensitizing effect of tamoxifen.

The Tamoxifen administration is in combination with cytotoxic drugs. High-dose tamoxifen has been turning up with very nice responses in cell culture assays. It turns up synergistic (cooperative) in brain tumors, lung cancers, ovarian cancers and the like.

High-dose tamoxifen significantly inhibits the P-glycoprotein (gatekeeper in the blood-brain barrier) multidrug resistant membrane pump, as well as inhibiting protein kinase C (preventing the increase in vascular resistance).

So in this case, tamoxifen acts as an agonist (makes the chemotherapy more potent) in ovarian cancer. It can "chemosensitize" tumor cells. In other words, tamoxifen can help chemotherapy be more effective, by being a resistance modifying drug.

Although a cytostatic agent like Tamoxifen does not induced programmed cell death (apoptosis) and the functional profiling platform usually does not give strong cell-death signals for Tamoxifen exposure in most tumors, high-dose Tamoxifen can be a potentiator (make more potent) for a cytotoxic drug and also act as an anti-angiogenic effect (limiting formation of new blood vessels).

The P-glycoprotein is not measured, per se. What is measured is a drug alone, a drug with high dose tamoxifen, and high dose tamoxifen alone. Sometimes a drug alone doesn't work and high dose tamoxifen alone doesn't work, but a drug PLUS high dose tamoxifen works brilliantly. This can be tested in any of the cell death endpoints: DISC, MTT, ATP, resazurin, or potentially others.