Researchers at Rutgers University have found that, in animal studies, a synthetic form of active vitamin D has a substantive preventive effect on the development of both estrogen receptor (ER)-positive and ER-negative breast cancers. Unlike many of the other synthetic vitamin D agents that have been tested in humans, this compound, known as Gemini 0097, shows no toxicity, they report.
The research team found that daily injections of Gemini 0097 cut growth of ER-positive cancer by 60 percent in rat studies, and reduced ER-negative breast cancer by half in mice.
"These are very promising findings, especially because no toxicity is observed," said researcher Hong Jin Lee, a graduate student at Rutgers. Lee works in the laboratory of lead investigator Nanjoo Suh, Ph.D., an assistant professor at the Susan Lehman Cullman Laboratory for Cancer Research at Rutgers, the State University of New Jersey. Suh said that Gemini 0097 likely did not cause the most common vitamin D toxicity, an overload of calcium in blood known as hypercalcemia, because the compound has an extra side chain of chemicals.
"It is quite different from the natural shape of active vitamin D," she said. "Because the binding affinity of Gemini 0097 with vitamin D receptor is low that may contribute to the lower toxicity, but the efficacy stays the same or even better."
Epidemiologic studies have shown that use of vitamin D is beneficial in preventing colon cancer, but studies in prostate and breast cancer have yielded mixed conclusions, Suh says.
Vitamin D is a pro-hormone that is produced in the skin after exposure to sunlight. Vitamin D dietary supplements are converted into an active, useful form by metabolism in the liver and kidneys. Although the active form of vitamin D has been tested as a cancer treatment, the higher doses needed for prevention or treatment have typically produced intolerable side effects in clinical trials, Suh says.
In this study, the researchers tested 60 novel Gemini vitamin compounds, with Gemini 0097 performing the best, Lee says.
In one set of studies, the researchers exposed rats to a mammary carcinogen, then injected groups of 15 animals with different doses of Gemini 0097. They found that the lowest dose had little effect but higher doses slowed the growth of resultant ER-positive tumors by 60 percent, compared with a group of control rats. Some treated rats developed small mammary tumors and some developed none at all, says Lee. "The data are very convincing," he said.
In a second, similar experiment in a mouse model of ER-negative breast cancer, mice treated with Gemini vitamin D had 50 percent fewer tumors than did control mice.
The researchers analyzed tumor samples from both the rats and the mice and discovered that Gemini 0097 prevents tumorigenesis by increasing expression of the p21 protein, which arrests the cell cycle, and by inducing insulin-like growth factor binding protein--3 (IGFBP-3), which slows down cell proliferation.
"These data are from animal studies, and we need more data before these compounds can be tested in humans," said Suh. "Still, we are hopeful that we have found a way of providing vitamin D without toxicity that has a significant effect on cancer prevention."
This research was presented at the 2008 Annual Meeting of the American Association for Cancer Research, April 12-16, 2008.
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