BETHESDA, MD—Data are mounting that new vitamin D analogs may be useful as therapy in cancer chemoprevention and in treatment, either alone or in combination with standard chemotherapy drugs.
Such analogs, termed deltanoids, blunt the inherent risk of hypercalcemia in vitamin D therapy; natural forms of vitamin D can increase serum calcium concentrations.
Scientists explored aspects of what has come to be known as the “vitamin D hypothesis” at an international conference at the National Institutes of Health here sponsored by the nonprofit Vitamin D Workshop, Inc., which is comprised of an international group of researchers on vitamin D and health who have been meeting regularly around the world since 1973.
In October 2003, the NIH cosponsored the “Vitamin D and Health in the 21st Century: Bone and Beyond” conference, which explored the role of vitamin D in osteoporosis and other diseases. Participants concluded that overall, Americans' current intakes of vitamin D may be too low for optimal health.
Concerns were also raised about Americans' use of sunscreens, which help to prevent skin cancer but block the sunlight from which the skin synthesizes vitamin D. The current daily vitamin D recommendations of the Food and Nutrition Board (FNB) of the National Academy of Sciences' Institute of Medicine were set in 1997: 200 IU up to age 50; 400 IU for people aged 51 to 70; and 600 IU for people over age 70.
Most multivitamin supplements contain 400 IU; the FNB is now considering whether recommended intakes of vitamin D need to be reviewed.
Undergirding recent studies on vitamin D's potential role in cancer is knowledge that the vitamin D receptor is found in many body tissues other than bone, including the prostate gland—site of a number of current vitamin D-related studies.
Also bolstering the new research is an increased understanding that active forms of vitamin D, including analogs, can:
* Boost immunity.
* Reduce cellular proliferation.
* Enhance cellular differentiation.
* Foster cellular apoptosis.
It may be, several speakers suggested, that vitamin D and its analogs act to maintain a normal cellular phenotype. Conversely, low circulating levels of vitamin D may promote abnormal cellular growth.
Epidemiologic and observational studies have also laid a foundation for research linking vitamin D and cancer. Clinical data link low circulating levels of the biologically active, hormonal metabolite of vitamin D—1,25-dihydroxyvitamin D3—with a higher risk of cancer incidence, especially of prostate cancer.
Prospective Study of About 50,000 Men
In a prospective study of vitamin D intake and cancer in American men, Edward Giovannucci, MD, Professor of Nutrition and Epidemiology at Harvard School of Public Health, and his colleagues found support for a protective effect of vitamin D against cancer incidence, and even more so against cancer mortality.
The researchers examined vitamin D intake in relation to the risk of total cancer incidence and mortality from 1986 to 2000 in nearly 50,000 men (initially cancer-free) participating in the Health Professionals Follow-Up Study.
In this study a higher recent intake of vitamin D—600 IU daily or greater vs less than 150 IU daily—was associated with a lower risk of cancer incidence and cancer mortality.
Dr. Giovannucci said this inverse association was apparent for both dietary vitamin D and vitamin D from supplements, and held for lung, prostate, colorectal, pancreatic, and other cancers combined.
African American race, obesity, and Northeast residence (where long winters reduce skin exposure to sunlight) were independent risk factors for cancer mortality, especially if vitamin D intake was low.
“Our findings support a benefit of vitamin D intake against cancer incidence and particularly mortality, especially in groups susceptible to vitamin D deficiency,” he concluded, adding, “High intake of retinol [a form of vitamin A found in multivitamins], which antagonizes vitamin D actions, partially offsets this benefit.
“Our findings suggest that hypovitaminosis D, which is more common in African Americans, obese individuals and those living in the Northeast of the United States, may partially explain high cancer mortality in these groups.”
Asked in an interview about potential vitamin D toxicity, Dr. Giovannucci said that virtually no evidence of vitamin D toxicity has been found at daily levels of 800 IU—well above current recommendations.
He also noted that even very high exposure to sunlight—which would increase the amount of vitamin D synthesized by the skin—has never produced a known case of hypercalcemia.
At the 2003 NIH conference, Robert P. Heaney, MD, Professor of Medicine at Creighton University and an attendee at the most recent meeting, presented data showing that the daily tolerable upper limit for vitamin D is about 2,000 IU.
Health Danger of Low Circulating Levels of Vitamin D in African Americans
Additional research at the NIH meeting pinpointed the health danger of low circulating levels of vitamin D in African American men and women (whose dark skin reduces their ability to synthesize vitamin D).
African Americans have higher incidence and mortality rates from certain cancers, especially prostate, breast, and colon, which are often attributed strictly to racial disparities in health care.
In a study of dietary intake and circulating vitamin D levels from the third National Health and Nutrition Examination Survey (NHANES III), researchers from the Center for Food Safety and Applied Nutrition of the Food and Drug Administration, analyzed vitamin D intake from milk, food, and supplements and circulating vitamin D levels.
The researchers found that on average the vitamin D serum level (nmol/L) was 79 for white adults and 48.20 for black adults.
“Compared with whites, blacks have higher incidence and mortality of certain aggressive cancers that are not attributed to disparities in health care,” the researchers concluded.
“The significant racial differences in vitamin D intake from all sources and poorer nutritional status…should raise strong concern given the strong association between poor vitamin D status and increased risk of cancer.”
Gary G. Schwartz, PhD, Associate Professor of Cancer Biology and Public Health Sciences at Wake Forest University School of Medicine, also provided support for the vitamin D hypothesis.
Noting that at every age the mortality rate from prostate cancer is about 50% higher in black men than in white men, he suggested that prostate cancer may be at least in part a “vitamin D deficiency disease” in certain populations.
Scandinavian men (whose exposure to sunlight is low due to their northern latitude) share a risk of prostate cancer similar to that of blacks, noted Dr. Schwartz, who is also Scientific Director of the Prostate Cancer Center of Excellence at Wake Forest's Comprehensive Cancer Center.
Prostate Gland Expresses Vitamin D Receptor & Synthesizes Active Vitamin D
It has been known since 1992 that the prostate gland expresses the vitamin D receptor, but recent research by Dr. Schwartz's group shows that the prostate also synthesizes active vitamin D-1,25(OH)-2D.
“Since the prostate makes its own active vitamin D essentially from sunlight, and active vitamin D inhibits growth and metastasis of prostate cells, lack of sunlight or vitamin D is a biochemically credible explanation for much of prostate cancer,” Dr. Schwartz explained.
In addition to the effects of reduced skin synthesis of vitamin D, it is possible that certain population groups could have vitamin D polymorphisms which place them at greater risk of prostate cancer, he continued.
“Intrinsically I think that if we can prevent rickets, we can prevent prostate cancer. The prostate does not live by androgens alone. Personally I've been trying to sensitize urologists to this for quite some time.”
But the challenge, said Dr. Schwartz, is trying to apply emerging knowledge about vitamin D and cancer to clinical practice.
For example, should physicians routinely measure circulating vitamin D levels, especially in African Americans and nursing home residents (whose skin is rarely exposed to sunlight)? Should oncologists recommend vitamin D supplements in addition to standard cancer treatments? If so, at what IU level?
Answers to these questions will hopefully evolve from current research.
“The evolution of our understanding of the role of vitamin D in cancer parallels our understanding of the role of vitamin D in rickets,” Dr. Schwartz said. “In both diseases, ecologic observations about solar radiation preceded experimental observations and were subsequently validated by them.”
Seasonal Variations in PSA
Seasonal variations in the rate of rise of prostate-specific antigen in 192 patients with untreated, clinically localized, low-to-intermediate grade prostate cancer provide further support for the vitamin D hypothesis.
A study presented by researchers from Mount Sinai Hospital, Toronto-Sunnybrook Regional Cancer Center, and Sunnybrook & Women's College Health Sciences Centre at the University of Toronto showed that the men's higher vitamin D levels in the spring quarter (April, May, June) when sunlight exposure is higher, were associated with a slower rise in PSA than was observed in the other quarters of the year, when exposure to sunlight was lower.
“These results are consistent with the vitamin D hypothesis, that the higher vitamin D nutrition associated with spring and summer can slow progression of certain forms of cancer,” the researchers concluded.
A study from the same research group showed that vitamin D in the form of cholecalciferol slowed the rate of rise in PSA levels in 15 men with relapsed prostate cancer.
Analog of Calcitriol Inhibits Prostate Cancer Cell Growth with Less Hypercalcemia Than Calcitriol in Early Studies
A number of studies presented at the meeting indicated that an analog of calcitriol, QW1624F2-2, inhibits prostate cancer cell growth both in the test tube and in laboratory animals (primarily mice) with less hypercalcemia than calcitriol.
In an Italian multicenter, randomized, placebo-controlled Phase II study of the vitamin D analog BXL-628 in men with benign prostatic hypertrophy, this analog arrested prostate cell growth, with what the researchers termed “excellent safety.” BXL-628 had already shown inhibition of prostate cell growth in rat and dog models before it was given to the human study participants.
A potential role for vitamin D analogs in colon, breast, bladder, pancreatic, and skin cancer is also being studied, according to data presented at the meeting.
Some—but not all—studies of vitamin D metabolites in serum have shown a higher risk of colon cancer in people whose oral intake of vitamin D was below the median.
These studies are consistent with four studies on the geographic association of sunlight intensity with age-adjusted colon cancer mortality rates, which showed markedly lower mortality rates in sunnier areas. In pancreatic cancer cell lines, the calcitriol analog paricalcitol has shown particular promise as a growth inhibitor.
Possible Synergy Between Vitamin D and Chemotherapy
Perhaps most hopeful clinically are studies showing a possibly synergistic effect between vitamin D or its analogs and currently used chemotherapy drugs.
Synergy has been observed between calcitriol and gemcitabine in multiple pancreatic tumor models. In vitro research in Milan has shown that calcitriol and doxorubicin were synergistic in the majority of bladder cancer cell lines tested.
Data presented by researchers from Roswell Park Cancer Institute showed that vitamin D compounds have been found to potentiate the anti-tumor effects of taxanes, platinum analogs, anti-metabolites, and receptor tyrosine kinase growth factor antagonists.
Clinical trials of each of these approaches are underway, including a randomized Phase III trial of docetaxel and calcitriol (oral, weekly high-dose) in androgen-independent prostate cancer.
While participants at the meeting agreed that much more work is needed to translate new information on vitamin D and cancer into clinical practice, they were optimistic that the field of vitamin D research on preventing and treating cancer is moving forward productively. As Dr. Schwartz remarked, it is now becoming accepted clinical wisdom that “the effects of vitamin D extend well beyond bones and stones.”