Vitamin D5 Ready for Clinical Trials
in Breast Cancer

A new vitamin D analog developed by IITRI's Dr. Rajendra Mehta in collaboration with the University of Illinois at Chicago (UIC) is ready for clinical trials, where it will be tested for its efficacy in the treatment of breast cancer.

Dr. Mehta, Assistant Vice-President and Manager of IITRI's Carcinogenesis and Chemoprevention Division, has conducted extensive preclinical studies in which the new analog, vitamin D5, has demonstrated chemopreventive and therapeutic activity against cancers in breast, colon and prostate.

New Analog a Close Cousin of More Common Vitamin D3

The new vitamin D analog differs by only a few atoms from the more frequently consumed form of vitamin D - vitamin D3 - that is present in milk and dietary supplements and is synthesized by the body in response to exposure to the sun.

The scientific community has studied the biological activity of vitamin D compounds for decades. Epidemiology studies suggest that people living in areas with more sunlight may have lower overall cancer incidences than do people living in areas with less sunlight. Vitamin D is created in the body when 7-dehydrocholesterol in the skin absorbs ultraviolet energy from the sun. The lower cancer rates among certain populations in tropical climates led to the theory that vitamin D might play a role in cancer prevention.

Vitamin D3 Shown Chemopreventive but Toxic

To test this theory, identification of the active vitamin D metabolite was essential. Once in the body, vitamin D3 is converted to an intermediate metabolite, 25-hydroxyvitamin D3, which is then converted into the active metabolite, 1,25-dihydroxyvitamin D3. In order to test the chemotherapeutic activity of vitamin D3, scientists incubated the active vitamin D3 metabolite with human cancer cells and then injected these cells into animals.

They found that while vitamin D3 did, in fact, inhibit the growth of cancer cells, the in vitro concentrations needed to inhibit cell growth were highly toxic. These very high concentrations of vitamin D3 induced large increases in free calcium in the body, a potentially fatal condition known as hypercalcemia.

The amount of 1,25-dihydroxyvitamin D3 obtained from normal sources is small enough to be regulated by enzymes that prevent too much of the metabolite from being formed. However, the quantity of exogenous 1,25-dihydroxyvitamin D3 necessary for therapy is hundreds of times greater than the amount required by the body for general maintenance and protection against disease. These high doses required for anticancer activity also resulted in significant toxicity.

Scientists Hunt for Safe, Efficacious Vitamin D3 Analog

In the effort to find a form of vitamin D that is both non-toxic and potent against cancer in its active metabolic state, researchers began synthesizing new vitamin D3 analogs, compounds similar to vitamin D3, but with minor changes in their chemical structure. In fact, synthetic organic chemists have created over 1,500 analogs of vitamin D3. Vitamin D is now classified into various primary forms as vitamin D2 through vitamin D7, as shown below. Vitamin D5 is reported to be the least toxic among these primary forms.

Allied Effort Key in Identifying Optimized Vitamin D Analog

Dr. Mehta, an expert in natural product chemoprevention research, began his search for a safe, potent vitamin D3 analog while working at UIC as a professor in the Departments of Surgical Oncology, Pharmacology and Human Nutrition.

Dr. Robert Moriarty, a synthetic organic chemist at UIC, happened to mention to Dr. Mehta that he had identified a compound in his research with absolutely no calcemic activity. While synthesizing a series of vitamin D analogs in order to find a compound with high calcemic activity, Dr. Moriarty synthesized an analog that had very little calcemic activity. This was just what Dr. Mehta needed for his own research. The collaboration between the two professors initiated Dr. Mehta's extensive research into the vitamin D5 analog.

Research Looks at Therapeutic and Preventive Activity

Dr. Mehta's research has focused on both therapeutic and preventive activity of vitamin D5. In therapy studies, animals are injected with human cancer cells, followed by treatment with vitamin D5 and observation for growth or regression of the cancer. In prevention studies, animals are exposed to a known carcinogen, treated with vitamin D5 prior to cancer development, and then observed to determine if the treatment prevents or delays cancer appearance. The new analog showed efficacy in both types of studies.

Working under the support of a breast cancer research grant from the United States Department of Defense, Dr. Mehta and his group supported the conduct of Investigational New Drug (IND)-enabling toxicity studies to characterize the toxicology of vitamin D5, to identify initial dose levels for use in clinical trials, and to satisfy Food and Drug Administration (FDA) requirements for the initiation of clinical trials. This work, which included subchronic toxicity studies in both rats and dogs, was performed at IITRI under the direction of IITRI's Senior Vice-President and Director, David L. McCormick, Ph.D., D.A.B.T.

Clinical Trials Target Therapy over Prevention

The IND application for the vitamin D5 analog is under consideration for approval by the FDA. Once approved, clinical trials will be conducted at UIC, where the drug has been formulated into a capsule by UIC pharmacists.

Dr. Mehta's hope, he said, is that one day people with a high risk of cancer can prevent its onset by taking a chemopreventive drug such as vitamin D5. However, significant challenges accompany chemoprevention trials in humans, not the least of which are requirements for very large study populations and long (and costly) observation periods, Dr. Mehta said.

Nevertheless, Dr. Mehta, who will conduct the data analysis for the clinical trials, asserts that preventive ability can be determined in cancer patients if the treatment prevents the development of new (additional primary) tumors or delays the re-growth of tumors that have been removed.

Plans for Preventive Studies in the Works

In the future, Dr. Mehta hopes for FDA approval to conduct preventive studies in gastroenterology patients at UIC and the VA hospital in collaboration with physicians there. He also plans to conduct a study at the University of California at Davis that will compare the efficacy of radiation alone versus a combination of radiation + vitamin D5 in prostrate cancer patients.

The work of Dr. Mehta and his group has proven that the active metabolite of vitamin D5 demonstrates anticancer efficacy at dose levels that are considerably less toxic than are effective doses of the active metabolite of vitamin D3. Clinical trials will investigate the potency of vitamin D5 in preventing, inhibiting and reversing the processes of carcinogenesis.

More information on IITRI's Carcinogenesis research services is available on the IITRI web site.