A newly synthesized vitamin D5 compound designated 1-alpha-(OH)D5, unlike the natural active metabolite [1-alpha,25(OH)2D3] of vitamin D3, strongly inhibited the development of precancerous cells in animal breast organ culture studies but did not raise calcium in the blood serum to toxic levels. According to Rajendra G. Mehta, PhD, University of Illinois, Chicago, and colleagues, this compound, the first of its type, may therefore prove useful in cancer prevention.
Reporting in the February 5th issue of the Journal of the National Cancer Institute, Mehta and coauthors point out that the biologically active (natural) form of vitamin D3 has been shown to effectively inhibit cancer cell growth in laboratory and animal studies, but a potentially fatal elevation of blood calcium levels has precluded its use in cancer patients. In addition to limiting cancer cell proliferation, vitamin D analogs have been shown to be capable of causing cancer cells to differentiate to a state in which they do not divide and even to promote tumor cell death through incompletely understood mechanisms. To date, add the researchers, the search for nontoxic vitamin D analogs has focused almost exclusively on analogs of vitamin D3, while other types of vitamin D (such as D4, D5, and D6) have been relatively unexplored.
In the current study, Mehta and coworkers synthesized an analog of vitamin D5 [1-alpha-(OH)D5], verified its purity, and compared its effect on calcium levels and cell proliferation to those of 1-alpha-25(OH)2D3. To test calcemic activity, baseline serum calcium levels were measured in vitamin D-deficient rats that then received one of various doses of either 1-alpha-(OH)D5 or 1-alpha,25(OH)2D3 for 14 days; control rats were treated with the vehicle solution only. At the end of this period, calcium levels were again measured. The vitamin D3 metabolite was found to be fourfold more calcemic than the vitamin D5 analog at an equivalent dosage (0.042 mcg/kg/d). Even at much higher doses, 1-alpha-(OH)D5 produced plasma calcium concentrations only 50% greater than those detected in the control rats.
Efficacy of New Analog in Preventing Mammary Lesions
An established organ culture model employing mouse mammary glands exposed to the known carcinogen 7,12-dimethlybenz[alpha]anthracene (DMBA) was used to evaluate the efficacy of the newly synthesized vitamin D5 analog in preventing the development of mammary lesions. 1-Alpha-(OH)D5 or 1-alpha,25(OH)2D3, in one of four concentrations, was added to the culture medium of separate groups of mammary glands, and untreated glands were used as controls.
The researchers found that both vitamin D analogs were highly effective in inhibiting the formation of precancerous mammary lesions--up to 100% at higher concentrations. The vitamin D3 analog was highly toxic at a concentration of 1.0 mcM, however, while the vitamin D5 analog was nontoxic at 10 times this level.
In addition, the researchers assesed the effects of the two analogs on the expression of vitamin D receptors (VDRs) and transforming growth factor-beta-1 (TGF-beta-1), which normally are poorly expressed in normal mouse mammary glands. Vitamin D receptors are believed to be involved both in the proliferation and differentiation of various cancer cells, and TGF-beta-1 production is often related to inhibition of cancer cell growth.
Exposing normal mammary glands in culture to either of the vitamin D analogs dramatically induced the expression of both VDRs and TGF-beta-1. The authors believe that this is the first report showing the possibility of cancer prevention by a vitamin D5 compound. They conclude that 1-alpha(OH)D5 is far less calcemic than 1-alpha,25(OH)2D3 but still very effective in preventing mammary lesions. They also believe that the results demonstrate, for the first time, the induced expression of TGF-beta-1 by a chemopreventive agent in normal mammary tissues. Taken together, say the authors, these results make the vitamin D5 analog a good candidate for in vivo chemoprevention studies.
Further Investigation of Vitamin D5 Analog Warranted
In an editorial accompanying the study report, Moray J. Campbell, PhD, and H. Phillip Koeffler, MD, Cedars-Sinai Medical Center, Los Angeles, concur that the results by Mehta et al demonstrate a therapeutic index sufficiently high to warrant further investigation of 1-alpha-(OH)D5 using other cancer cell types and model systems. According to the editorialists, 1-alpha(OH)D5 is one of several vitamin D analogs that may be promising candidates for clinical study.