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
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.