Researchers at Johns Hopkins have developed a modified form of vitamin D and determined that it helps delay the onset and reduce the number of skin cancers in lab mice. Unlike vitamin D, though, the new compound does not cause calcium to seep from the bones.
If not for the calcium loss problem, large doses of vitamin D could be used to reduce the odds of developing cancer in patients whose medical history, genetic heritage or environmental exposures put them at increased risk. Depending on the results of further tests in animals and potential tests in humans, the new compound and others to follow it may provide an important alternative approach to reducing cancer risk for such patients.
Gary Posner, Scowe Professor of Chemistry in the Krieger School of Arts and Sciences and one of the new compound's creators, described work to design and test the compounds at a meeting of the American Chemical Society last month in Washington, D.C.
In the July/August issue of Carcinogenesis, Posner and Thomas Kensler, a professor at the School of Public Health, published results of tests in mice of four modified forms of vitamin D, called deltanoids or vitamin D analogs. The deltanoids were applied to the skin of mice also treated with a carcinogen.
All four deltanoids diminished the number of skin tumors without stunting the animals' growth or making them seriously ill, which are typical side effects of very large doses of vitamin D. The most effective preventive compound was a doubly modified "hybrid" compound that contained fluorine.
The new deltanoids are, for the most part, identical to vitamin D, which is normally generated in the skin during exposure to sunlight. In several areas, though, Posner and his students have given the compounds' molecular structures several small "tweaks."
"We call our work molecular architecture because at the submicroscopic level we are altering the structures of known compounds or designing new compounds from scratch," Posner explains.
Those alterations can include adding components to, taking things away from and reorienting parts of the molecule.
"It's still a science and an art combined," Posner explains. "It's not yet possible for anyone to go from a new chemical structure and to predict in advance the biological properties of that new structure."
This inability of molecular architects to predict exactly the results of their design changes can sometimes force them to rely on their intuitive sense of which change will produce the desired result. But the design process is also rational, Posner emphasizes, because it is based to the greatest extent possible on principles established through prior experimentation. Earlier research in the deltanoids included many efforts by pharmaceutical companies to improve vitamin D.
"What we did was take some of the best structural changes that large pharmaceutical companies have made public," Posner says, "and incorporate those changes with a structural change that we discovered here 10 years ago in a different portion of the molecule."
Posner's team found that if they added a methylene group, composed of one extra carbon atom and two hydrogen atoms, to an area of the vitamin D molecule known as the A ring, the molecule caused much less calcium loss.
Based on the research of another lab, Posner's group also added two fluorine atoms to the molecule at an ideal point to reduce the body's ability to break down and metabolize the vitamin D analogs. This not only reduces the levels of potentially harmful metabolites produced by the analogs, it also keeps the analogs active in the body longer.
The changes are all small compared to the size of the vitamin D molecule, which has a total of 27 carbon atoms. But they make a significant difference in its effects.
"You might think you'd have to change large portions of the molecule to change its biological effects, but it's well-known that you can do that by changing small portions of the molecule," Posner says.
Further animal tests of the analog on different types of tumors are planned in Kensler's lab. If the new tests and tests in humans prove successful, doctors might one day be able to consider treating patients at high risk for cancer with the compound, probably applying it as a topical gel.
Meanwhile, Posner's lab is already at work on yet another generation of improved deltanoids.
"There's a lot of trial and error," he says. "My research group has, over the years, made about 100 different vitamin D analogs. And the winners are probably limited to 10. If you consider the more general issue in the pharmaceutical industry, though--going from the bench to a drug--typically it's one in many thousands of compounds. And that gives you a feeling for just how far rational design can or can't come."
This research was funded in part by grants from the National Cancer Institute of the National Institutes of Health.