Anti-angiogenic activity and VEGF pathway inhibition of Tarceva
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.
Weisenthal Cancer Group, Huntington Beach, CA 92647, USA. [email][email protected]
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.
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