PITTSBURGH, Jan. 20 -- A steroid drug enhances the ability of a vitamin D analogue to kill cancer while reducing a potentially serious side effect of vitamin D therapy, according to investigators at the University of Pittsburgh Cancer Institute (UPCI). Their findings on dexamethasone and the vitamin D derivative, 1,25-dihydroxyvitamin-D3, (1,25-D3), in an animal model are reported in the Jan. 21 issue of the Journal of the National Cancer Institute.
"We were very excited to find that not only did dexamethasone reduce hypercalcemia associated with 1,25-D3 , it actually improved the ability of 1,25-D3 to kill cancer cells in an animal model," noted Candace Johnson, Ph.D., study investigator, interim director for basic research at UPCI and co-director of UPCI's Molecular Oncology/Drug Discovery Program.
"We have previously shown that 1,25-D3 effectively halts the growth of cancer in animals, and we have conducted preliminary trials of this agent in men with advanced prostate and other cancers. However, the use of 1,25-D3 has been limited because this drug causes a potentially life-threatening increase of calcium in the blood," said Donald Trump, M.D., an investigator on the study, deputy director for clinical investigations at UPCI and director of the UPMC Health System's division of medical oncology.
UPCI investigators were among the first to describe the anti-tumor activity of vitamin-D compounds, or analogues, and showed that they arrest cancer growth in culture and in animals. While other researchers had previously shown the effect of vitamin D analogues in leukemia cells, Dr. Johnson and Dr.Trump were among the first to demonstrate the efficacy of these agents against solid tumors such as prostate cancer and head and neck cancers. Currently, the UPCI team is conducting a clinical protocol combining a steroid with 1,25-D3 for advanced cancer.
Dexamethasone appears to enhance 1,25-D3 activity by 'telling' tumor cells to increase their production of vitamin D receptors and by increasing the ability of existing vitamin D receptors to bind with 1,25-D3. As a result, more 1,25-D3 may enter tumor cells, where it suppresses tumor growth.
In the current study using mice, the researchers found that the combination of dexamethasone and 1,25-D3 was better than 1,25-D3 alone at preventing injected tumor cells from growing into full-fledged tumors. This drug combination also worked better than 1,25-D3 alone to prevent already established tumors from growing any further. In both sets of experiments, the addition of dexamethasone to 1,25-D3 also significantly reduced blood calcium levels.
1,25-D3 causes buildup of blood calcium in several ways. It increases calcium release from bones and calcium absorption from the intestines. At the same time, it causes kidneys to retain calcium so it is not released in urine.
Hypercalcemia may result in confusion, constipation, nausea, vomiting, fatigue, kidney damage and even coma or death.
In research published late last year, Drs. Johnson and Trump also showed that 1,25-D3 bolsters the anti-tumor activity of a standard chemotherapy drug, cisplatin, in animals with cancer. The investigators are currently incorporating these findings into clinical trials.
One of 31 National Cancer Institute-designated cancer centers in the country, UPCI is recognized for its excellence in cancer detection, diagnosis, treatment and patient education and care. UPCI is internationally recognized for its translational research, wherein basic laboratory findings are rapidly developed into novel cancer therapies.
For additional information about UPMC Health System and UPCI, please access http://www.upmc.edu.
Journal
JNCI Journal of the National Cancer Institute