PITTSBURGH, June 1 -- Scientists at the University of Pittsburgh have discovered how a novel form of vitamin K exerts its cancer-killing effects in primary liver cancers, which are notoriously resistant to chemotherapy. The research results, published in the May issue of The Journal of Biological Chemistry, describe an important new way to treat, and possibly prevent, cancer by triggering programmed cell death.
"Our finding is extremely important if we are to maximize the use of vitamin K compounds against cancer," noted Brian Carr, M.D., Ph.D., FRCP, professor of surgery in the Thomas E. Starzl Transplantation Institute and director of the Liver Cancer Center at the University of Pittsburgh Cancer Institute (UPCI). "Through our ongoing research, we now know that the vitamin K compounds not only can kill liver cancers, but also can destroy other types of cancer in tissue cultures, including breast cancer and melanoma. They do so by a quite novel growth-regulating mechanism."
"One of the attractive features of this unique compound is that it appears to stop cancer cell growth without producing toxicity. We now are testing this compound against cancers in rats, and given positive results, we hope to begin clinical trials of this agent within two years."
The Pitt research team found that a vitamin K analog, Compound 5 (Cpd 5), causes an imbalance in the normal activity of enzymes that control the addition or removal of small molecules called phosphate groups from selected proteins inside cells. Specifically, Cpd 5 blocks the activity of enzymes called protein-tyrosine phosphatases, which normally remove phosphate groups from selected proteins inside liver cancer cells. However, Cpd 5 does not interfere with another group of enzymes called protein tyrosine-kinases, which add phosphate groups to these same proteins. The result is an excess of what are called tyrosine phosphorylated proteins, which trigger a variety of activities within cells. They exert anti-cancer effects by inducing the shutdown and subsequent death of a cell, commonly referred to as programmed cell death.
Liver cancer is thought to be one of the three commonest cancers worldwide. The disease caused about 15,000 U.S. deaths in 1997 alone. Major causes of this cancer include infection with either hepatitis B or C or chronic alcohol consumption. In the United States and other developed countries, liver cancer may be treated by taking out the area of the liver containing a tumor or by surgically removing the diseased organ and transplanting a new one. However, liver transplantation is costly and often unavailable due to the scarcity of donated organs, or due to the advanced nature of the cancer at diagnosis.
"By providing this modified vitamin K to individuals at known risk of developing liver cancer, we might be able to reduce the incidence of this devastating illness. By treating liver cancer with this agent, we possibly could remove some individuals with this disease from transplant waiting lists, if it is as effective in humans as it is experimentally," said Dr. Carr.
Dr. Carr and his colleagues recently reported that Cpd 5 can inhibit liver regeneration in rats that had part of their livers removed. The animals suffered no toxic side effects.
Researchers at UPCI are at the forefront of experimental work using vitamins A, D and K to prevent and treat various forms of cancer in laboratory animals and in clinical trials with patients. As one of 31 National Cancer Institute-designated comprehensive cancer centers, UPCI is recognized for its interdisciplinary approach to cancer prevention, detection, diagnosis, treatment, education and community outreach and for its commitment to translational research that brings new cancer therapies from the laboratory bench to the patient's bedside as rapidly as possible.
The new vitamin K is not in clinical testing at this time. However, patients and physicians can contact the UPCI's Cancer Information and Referral Service for more information about cancer and ongoing clinical trials by calling 1 (800) 237-4PCI(4724) or (412) 624-1115. Inquirers also can visit UPCI's website at http://www.upci.upmc.edu.