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:: Angiogenesis in cancer

How angiogenesis complicates cancer

Angiogenesis performs a critical role in the development of cancer. Solid tumors smaller than 1 to 2 cubic millimeters are not vascularized. To spread, they need to be supplied by blood vessels that bring oxygen and nutrients and remove metabolic wastes.

Beyond the critical volume of 2 cubic millimeters, oxygen and nutrients have difficulty diffusing to the cells in the center of the tumor, causing a state of cellular hypoxia that marks the onset of tumoral angiogenesis.

New blood vessel development is an important process in tumor progression. It favors the transition from hyperplasia to neoplasia i.e. the passage from a state of cellular multiplication to a state of uncontrolled proliferation characteristic of tumor cells.

Neovascularization also influences the dissemination of cancer cells throughout the entire body eventually leading to metastasis formation.The vascularization level of a solid tumor is thought to be an excellent indicator of its metastatic potential.

The molecular factors involved in the stimulation of blood vessel growth are described in detail in The process of angiogenesis.

Shortcomings of standard therapies

Standard therapies to combat cancer are usually aimed at interfering with the cellular replication process which is accelerated in tumors. Despite the efforts made since 1971 to fight cancer -- the year the United States declared war on the disease -- new cases of most cancers have increased significantly. Ninety percent of all cancers are solid tumors and thus depend on angiogenesis to support their growth.

Resistance to treatment is a major issue in oncology. In hormone-dependent cancer for instance, after standard anti-hormonal therapy, it is common to see a recurrence of cancer. This occurs when a malignant cell is transformed a second time, thus making its replication independent of hormones. The same phenomenon takes place with cancers treated with chemotherapy. Often a transformed cell exposed to a powerful chemical agent goes through a mutation, giving it a selective advantage for growth, such as the production of a growth factor or resistance to chemotherapeutic agents.

It has also been shown that the resection of a primary tumor is often accompanied by metastases caused by a systemic disturbance of the angiogenic balance of the body. All these standard therapies could profit from a concomitant treatment that would restrict latent tumors in a prevascular phase.

Antiangiogenesis as a strategy against cancer

As early as the 1970s, Dr. Judah Folkman of the Harvard Medical School suggested inhibiting new blood vessel formation as a way to fight cancer.

The malignant tissue would be deprived of its oxygen and nutrient supply, as well as be unable to eliminate metabolic wastes. This in turn would inhibit tumor progression and metastatic progression that accompanies most advanced cancers. These are the main steps of the angiogenic process that can be interrupted:
  • Inhibiting endogenous angiogenic factors, such as bFGF (basic Fibroblast Growth Factor) and VEGF (Vascular Endothelial Growth Factor)

  • Inhibiting degradative enzymes (Matrix Metalloproteinases) responsible for the degradation of the basement membrane of blood vessels

  • Inhibiting endothelial cell proliferation

  • Inhibiting endothelial cell migration

  • Inhibiting the activation and differentiation of endothelial cells

However, the challenge is to develop an antiangiogenic factor that does not affect the existing vasculature.

Neovastat is an inhibitor of angiogenesis

A number of studies have shown Neovastat to have antiangiogenic properties. The mechanisms of action include:
  • Inhibiting degradative Matrix Metalloproteinases,

  • Blocking receptor sites for the angiogenic growth factor VEGF, which prevents endothelial cells from proliferating, migrating, and organizing to form new blood vessels in vitro.

As well, clinical and pre-clinical studies show Neovastat can be used alone or in combination with other therapies. Clinical experience with 540 patients, some of whom have been administered the drug for almost four years, have confirmed Neovastatís excellent safety and tolerability profile in monotherapy and in concomitant chemotherapy and radiotherapy.

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