Between 1970 and 1994, cancer claimed the lives of about 0.5 million Americans every year. Incidence and mortality rates remain high today and the development of therapeutic strategies for the prevention and treatment of cancer thus represents a key priority for the pharmaceutical industry (see "Cancer Treatment 2002" for a full analysis of current and future pharmaceutical approaches to cancer).

Of the 160,000 patients seen yearly in the United States with colon cancer, as many as 40-50% develop metastatic liver cancer. Although primary colorectal and gastric cancer accounts for about 50% of patients with metastatic liver cancer, primary breast and lung cancer also frequently metastasizes to the liver. Once secondary tumors form in the liver cure is rare and since together, breast, lung and colorectal cancers account for a large proportion of cancer cases, liver metastasis represents a major cause of death and a key, yet untapped aspect of cancer therapeutics.

Angiogenesis, the formation of new blood vessels, is crucial to a number of physiological processes such as reproduction, development and tissue repair, as well as in disease states including cancer, rheumatoid arthritis and other inflammatory diseases. Consequently angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion (click here to access our recent feature “New Lines of Attack in Cancer: Inhibitors of Angiogenesis”). Angiogenesis is a well-programmed cascade of events, which contains a number of distinct steps. One such step involves the migration and adhesion of endothelial cells to areas that are destined to become hyper-vascularized.

Although anti-angiogenic therapies have proven to be effective in preclinical models, long-term, high-level, and sustained expression of angiogenesis inhibitors, such as angiostatin, is necessary to prevent dormant tumors from becoming active again.

Since high level and prolonged expression of angiostatin in the liver is an attractive approach for the treatment of metastatic liver cancer, researchers from the University of Hong Kong have been working towards the development of a viral vector encoding mouse angiostatin. This group has found that after intraportal delivery of this vector, high-level, stable transgene expression of angiostatin lasting for at least 6 months was observed locally in hepatocytes. Gene transfer of angiostatin via the portal vein led to significant suppression of the growth of both nodular and metastatic EL-4 lymphoma tumors established in the liver and prolonged the survival time of the mice. The growth of neovessels was inhibited significantly, and extensive apoptosis of tumor cells was observed. The anti-angiogenic activity of angiostatin was independent of vascular endothelial growth factor. The viral vector did not appear to be toxic to mice, and there was no detectable apoptosis of hepatocytes. These encouraging results warrant future investigation of the use of antiangiogenic gene therapy for targeting unresectable liver metastases, especially after surgical removal of primary tumors.

Entry date Monday, June 30, 2003

Adapted from Xu et al, Hepatology. 2003 Jun;37(6):1451-60.

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