New Vitamin D Compound Reduces Cell Proliferation Without Toxicity

April 1, 1997

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

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 precancerouscells in animal breast organ culture studies but did not raise calciumin the blood serum to toxic levels. According to Rajendra G. Mehta, PhD,University of Illinois, Chicago, and colleagues, this compound, the firstof its type, may therefore prove useful in cancer prevention.

Reporting in the February 5th issue of the Journal of the NationalCancer Institute, Mehta and coauthors point out that the biologicallyactive (natural) form of vitamin D3 has been shown to effectivelyinhibit cancer cell growth in laboratory and animal studies, but a potentiallyfatal elevation of blood calcium levels has precluded its use in cancerpatients. In addition to limiting cancer cell proliferation, vitamin Danalogs have been shown to be capable of causing cancer cells to differentiateto a state in which they do not divide and even to promote tumor cell deaththrough incompletely understood mechanisms. To date, add the researchers,the search for nontoxic vitamin D analogs has focused almost exclusivelyon analogs of vitamin D3, while other types of vitamin D (suchas D4, D5, and D6) have been relativelyunexplored.

In the current study, Mehta and coworkers synthesized an analog of vitaminD5 [1-alpha-(OH)D5], verified its purity, and comparedits effect on calcium levels and cell proliferation to those of 1-alpha-25(OH)2D3.To test calcemic activity, baseline serum calcium levels were measuredin vitamin D-deficient rats that then received one of various doses ofeither 1-alpha-(OH)D5 or 1-alpha,25(OH)2D3for 14 days; control rats were treated with the vehicle solution only.At the end of this period, calcium levels were again measured. The vitaminD3 metabolite was found to be fourfold more calcemic than thevitamin D5 analog at an equivalent dosage (0.042 mcg/kg/d).Even at much higher doses, 1-alpha-(OH)D5 produced plasma calciumconcentrations 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 exposedto the known carcinogen 7,12-dimethlybenz[alpha]anthracene (DMBA) was usedto evaluate the efficacy of the newly synthesized vitamin D5analog in preventing the development of mammary lesions. 1-Alpha-(OH)D5or 1-alpha,25(OH)2D3, in one of four concentrations,was added to the culture medium of separate groups of mammary glands, anduntreated glands were used as controls.

The researchers found that both vitamin D analogs were highly effectivein inhibiting the formation of precancerous mammary lesions--up to 100%at higher concentrations. The vitamin D3 analog was highly toxicat a concentration of 1.0 mcM, however, while the vitamin D5analog was nontoxic at 10 times this level.

In addition, the researchers assesed the effects of the two analogson the expression of vitamin D receptors (VDRs) and transforming growthfactor-beta-1 (TGF-beta-1), which normally are poorly expressed in normalmouse mammary glands. Vitamin D receptors are believed to be involved bothin the proliferation and differentiation of various cancer cells, and TGF-beta-1production is often related to inhibition of cancer cell growth.

Exposing normal mammary glands in culture to either of the vitamin Danalogs dramatically induced the expression of both VDRs and TGF-beta-1.The authors believe that this is the first report showing the possibilityof cancer prevention by a vitamin D5 compound. They concludethat 1-alpha(OH)D5 is far less calcemic than 1-alpha,25(OH)2D3but still very effective in preventing mammary lesions. They alsobelieve that the results demonstrate, for the first time, the induced expressionof TGF-beta-1 by a chemopreventive agent in normal mammary tissues. Takentogether, say the authors, these results make the vitamin D5analog 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 indexsufficiently high to warrant further investigation of 1-alpha-(OH)D5using other cancer cell types and model systems. According to the editorialists,1-alpha(OH)D5 is one of several vitamin D analogs that may bepromising candidates for clinical study.