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Anti-angiogenic activity and VEGF pathway inhibition of Tarceva

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

The AngioRx Assay has identified potential responders to Avastin, Nexavar, Sutent and other anti-angiogenic drugs and assessed previously unanticipated direct and potentiating anti-angiogenic effects of targeted therapy drugs such as Tarceva and Iressa.

Tarceva is a tyrosine kinase inhibitor. However, it also has an anti-angiogenic effect on cancer cells. There are a number of classes of drugs that target angiogenesis (VEGF). At the protein level is Avastin. At the tyrosine kinase level is Iressa, Nexavar, Sutent and Tarceva. At the intracellular metabolic pathway mTOR level is Afinitor and Torisel.

When chemotherapy drugs work, they often cause tumors to shrink a lot, sometimes even making them disappear. But anti-angiogenesis drugs don't seem to work in the same way. In some cases they shrink tumors, but in others they just seem to stop them from growing any larger.

Newer approaches to treatment that combine anti-angiogenesis drugs with chemotherapy, other targeted drugs, or radiation may work better than using them alone. For instance, early studies that tested the drug Avastin by itself did not find that it helped people with cancer to live longer. But later studies found that when it was combined with chemotherapy to treat certain cancers, it helped people (some subsets of patients) live longer than if they got the chemotherapy alone.

Doctors aren't sure why this is the case. One theory is based on the fact that chemotherapy drugs may have a hard time getting to cells in the middle of tumors. Tumor blood vessels grow in a short amount of time and in an abnormal environment, so they are not as well-made and stable as normal blood vessels.

Because of this, they tend to be leaky. This affects how well drugs can reach the inside of the tumor. The theory is that anti-angiogenesis drugs may somehow stabilize these tumor blood vessels for a short period of time, allowing the chemotherapy to reach more tumor cells and be more effective.

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.

Source

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.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2008.01955.x/full

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

Cancer Res. 2007 Nov 15;67(22):11012-20.

Erlotinib (Tarceva) antagonizes ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance.

Shi Z, Peng XX, Kim IW, Shukla S, Si QS, Robey RW, Bates SE, Shen T, Ashby CR Jr, Fu LW, Ambudkar SV, Chen ZS.

Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York 11439, USA.

Abstract

It has been reported that gefitinib (Iressa), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has the ability to modulate the function of certain ATP-binding cassette (ABC) transporters and to reverse ABC subfamily B member 1 (ABCB1; P-glycoprotein)- and ABC subfamily G member 2 (ABCG2; breast cancer resistance protein/mitoxantrone resistance protein)-mediated multidrug resistance (MDR) in cancer cells. However, it is unknown whether other EGFR TKIs have effects similar to that of gefitinib (Iressa). In the present study, we have investigated the interaction of another EGFR TKI, erlotinib (Tarceva), with selected ABC drug transporters. Our findings show that erlotinib (Tarceva) significantly potentiated the sensitivity of established ABCB1 or ABCG2 substrates and increased the accumulation of paclitaxel or mitoxantrone in ABCB1- or ABCG2-overexpressing cells. Furthermore, erlotinib (Tarceva) did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in all cells and was unable to reverse MRP1-mediated MDR and had no effect on the parental cells. However, erlotinib (Tarceva) remarkably inhibited the transport of E(2)17 beta G and methotrexate by ABCG2. In addition, the results of ATPase assays show that erlotinib (Tarceva) stimulated the ATPase activity of both ABCB1 and ABCG2. Interestingly, erlotinib (Tarceva) slightly inhibited the photolabeling of ABCB1 with [(125)I]iodoarylazidoprazosin (IAAP) at high concentration, but it did not inhibit the photolabeling of ABCG2 with IAAP. Overall, we conclude that erlotinib (Tarceva) reverses ABCB1- and ABCG2-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1 and ABCG2. These findings may be useful for cancer combinational therapy with erlotinib (Tarceva) in the clinic.

PMID: 18006847 [PubMed - indexed for MEDLINE]

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

The discovery of ABC transporters (superfamily of carrier proteins) was recognized as the basis for the human P-glycoprotein drug resistance mechanisms. The over expression of P-glycoprotein involved in cellular transport is a frequent cause of multiple drug resistance. A genetic predisposition causes multiple proteins to dot the surface of tumor cells. These proteins are known as P-glycoprotein (PGP). PGP is a transmembrane efflux pump. It pumps harmful things from the inside of the cell to the outside of the cell. As soon as drugs enter the cancer cells, the PGP pumps start pumping the drugs out.

The presence of P-glycoprotein signals that the patients would not respond well to chemotherapy. PGP is primarily responsible for inducing multi-drug resistance, in which the tumors become resistant to many chemotherapy drugs. PGP effectively pumps the drug out of tumor cells before it has time to kill the cells. Harpole et al, found that patients with PGP survived 20.9 months on average, while patients without PGP had an average survival of more than 5 years after diagnosis.

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).

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).

In cell functional analysis that Rational Therapeutics and Weisenthal Cancer Group provide, 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 they use: DISC, MTT, ATP, resazurin, or potentially others.

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

Source: Rational Therapeutics, Inc. and Weisenthal Cancer Group

Research by Giovanna Ames, Piet Borst, Peter Wielinga, Michael Dean, et al and others, has recognized ABC (ATP-Binding Cassette) genes that represent the largest family of transmembrane proteins (transporters) as the basis for P-glycoprotein drug resistance mechanisms. The over expression of P-glycoprotein (PGP) involved in cellular transport is a frequent cause of multiple drug resistance. In many cases, PGP is responsible for a patient's decreased sensitivity to anti-cancer drugs. As soon as the drug enters the cancer cells, the PGP pumps start pumping the drug out. PGP effectively pumps the drug out of tumor cells before it has time to kill the cells. Tarceva is not exported from the PGP and other ABC transporters placed at the luminal membrane of brain capillaries. Thus the higher concentration of Tarceva in the central nervous system (CNS).

The Human ATP-Binding Cassette (ABC) Transporter Superfamily

http://www.ncbi.nlm.nih.gov/books/NBK31/

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

P-glycoprotein (PGP) is a plasma membrane protein which acts as a localized drug transport mechanism, actively exporting drugs out of the cell. The effects of PGP on the distribution, metabolism and excretion of drugs -- including protease inhibitors -- in the body is great. PGP activity decreases the intracellular concentration of cancer drugs, enabling resistance to develop to them.

The normal physiological function of PGP in the absence of therapeutics or toxins is unclear. Studies of MDR-1 knock-out mice (mice bred in the lab specifically for the absence of the MDR-1 gene and, therefore, no PGP activity) show that they have normal viability, fertility and a range of biochemical and immunological parameters.

Predictably, they do have delayed kinetics and clearance of vinblastine, and they accumulate high levels of certain drugs (vinblastine, ivermectin, cyclosporin A, dexamethasone and digoxin) in their brains. The mice also demonstrated marked increases in the levels of these drugs in the tests, ovaries and adrenal gland compared with wild-type mice. It has been reported that some MDR-1a knock-out mice develop a severe, spontaneous intestinal inflammation similar to human inflammatory bowel disease.

The majority of published data suggest that PGP acts as a transmembrane pump which removes drugs from the cell membrane and cytoplasm. It has further been proposed that PGP acts like a hydrophobic vacuum cleaner or "flippase," transporting drugs from the inner leaflet of the plasma membrane lipid bilayer to the outer leaflet or to the external medium.

There have been various attempts to classify compounds based on their effect on or interaction with PGP. A number of chemicals, including anticancer drugs, have been categorized based on their effect on ATPase activity of human PGP. 

Class I compounds in low concentrations stimulate ATPase activity and in high concentrations inhibit it. Kinetic analyses show they have high affinity for the active site and low affinity for the inhibitory site. They include vinblastine, verapamil and taxol.

Class II compounds stimulate ATPase activity in a dose-dependent manner without any inhibition and interact only with the active site. They include bisantrene, valinomycin and diltiazem.

Class III compounds, which bind to the inhibitory site with high affinity, inhibit both basal and verapamil-stimulated ATPase activity. They include cyclosporin A, rapamycin and gramicidin D.

Some studies support a model of PGP in which there is a region or multiple regions of interaction rather than one or two simple binding sites. Molecules interacting with PGP may be classified as "substrate" or "antagonist."

It has also been demonstrated that one possible mechanism of action for PGP-mediated resistance to chemotherapeutic agents is through gene rearrangement.

Source: Treatment Action Group

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