A steroid drug enhances the ability of a vitamin D analog 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 were reported in the January 21, 1998, 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, PhD, study investigator, interim director for basic research at UPCI, and codirector of UPCIs Molecular Oncology/Drug Discovery Program.
Previous Findings Show Antitumor Effects of 1,25-D3
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, md, an investigator on the study, deputy director for clinical investigations at UPCI, and director of the UPMC Health Systems division of medical oncology.
UPCI investigators were among the first to describe the antitumor activity of vitamin D analogs and showed that they arrest cancer growth in culture and in animals. While other researchers had previously shown the effect of vitamin D analogs in leukemia cells, Drs. Johnson and 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.
Current Study Findings
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 in preventing injected tumor cells from growing into full-fledged tumors. The drug combination also worked better than 1,25-D³ alone in stopping 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.
The 1,25-D³ analog causes a build-up of blood calcium in several ways. It increases calcium release from bones and calcium absorption by the intestines. At the same time, it causes kidneys to retain calcium so it is not released in urine.
In research published late last year, Drs. Johnson and Trump also showed that 1,25-D³ bolsters the antitumor activity of cisplatin (Platinol) in animals with cancer. The investigators are currently incorporating these findings into clinical trials.