Cancer Epidemiology Biomarkers & Prevention Vol. 8, 107-109, January 1999
© 1999 American Association for Cancer Research
An International Evaluation of the Cancer Preventive Potential of Vitamin A1
Harri Vainio2 and
Matti Rautalahti
Unit of Chemoprevention, International Agency for Research on Cancer, Lyon, France
 |
Abstract
|
|---|
The IARC convened a Working Group of experts in May 1998 to evaluate the
cancer preventive potential of vitamin A and to compile the third
volume of the IARC Handbooks of Cancer Prevention. The
handbook is intended to provide a comprehensive review of the relevant
information in the published scientific literature through April 1998
on the role of vitamin A in cancer prevention. The focus of this
critical review and commentary is on retinol and the retinyl esters.
Much of the scientific literature in this field overlaps with studies
involving vitamin A metabolites, vitamin A precursors, and studies of
total dietary vitamin A (which is a combination of preformed vitamin A
and its precursors), so work from this wide range of research is
included in this review when it is deemed relevant to our understanding
of the effects of retinol or retinyl esters on cancer development. The
observed effects of preformed vitamin A on cell and organ culture, on
animal models, in dietary observational epidemiological studies, and in
human intervention studies was reviewed in the meeting. In summary,
there is little evidence that vitamin A intake has any substantial
cancer-preventive effects.
|
Introduction
|
|---|
In 1926, Fujimaki called attention to a possible
relationship between vitamin A deficiency and carcinogenesis. In the
next 2 decades, retinol deficiency was found to inhibit the
differentiation of mesenchymal cells to vascular cells in chick embryo
(1)
. Subsequently, the roles of retinoic acid and its 9-cis
isomer were established in controlling cell differentiation, growth,
and reproduction (2–4)
. In the past 20 years, vitamin A has been
extensively studied as a cancer chemopreventive agent. Several reviews
of chemoprevention studies using vitamin A in cell culture, in animals,
and in man have been published in recent years (5–14)
.
Vitamin A deficiency is clearly a continuing public health problem in
many areas of the world (15)
. Because vitamin A deficiency can lead to
an increased risk for many health problems including infections and
blindness, programs to supplement and fortify foods for undernourished
populations continue to be an important public health priority.
Patterns of cancer mortality worldwide do not correspond strongly to
patterns of vitamin A deficiency except, perhaps, for cancers of the
liver and stomach, sites that are thought to be etiologically related
to both infectious and nutritional factors. The public health problem
of vitamin A deficiency and the potential role of vitamin A in cancer
prevention are, therefore, two important but distinctly different
issues.
In much of the nutritional scientific literature, "vitamin A" is
used as a generic term that refers to both preformed vitamin A (largely
all-trans-retinol and its esters) and to some of the
carotenoids. The third IARC Handbook of Cancer Prevention is
focused on the cancer-preventive effects of the preformed vitamin A
compounds, principally retinol and retinyl esters. Volume 2 in the IARC
handbook series reviewed the carotenoids (16)
, and the forthcoming
volume 4 will review in more detail retinoic acid, other retinoid
metabolites, and synthetic retinoids.
|
Issues in Research on Vitamin A and Cancer
|
|---|
It is clear that an important limitation of the use of preformed
vitamin A in cancer prevention in humans is the toxicity that is seen
at high doses. Toxicities are seen in various organs, including the
skin, circulation (e.g., hypertriglyceridemia), liver,
nervous system, and bones. Of particular concern regarding the
widespread use of preformed vitamin A is the apparent sensitivity of
the developing embryo to teratogenesis at levels of supplemental
retinyl palmitate as low as 25,000 IU/day. This toxicity of preformed
vitamin A has prompted the development of literally thousands of
synthetic retinoids designed to have more specific beneficial
properties, but with lower toxicity potential. An active retinoid
without teratogenic potential is yet to be identified, however.
One of the particular challenges in interpreting studies of vitamin A
effects on cancer is that studies have been done at widely differing
levels of vitamin A nutritive status. For instance, several studies
have indicated greater effects with supplementation in animals that
were first fed vitamin A-deficient diets than among animals on normal
diets. Such experimental studies involving humans who are maintained in
a vitamin A-deficient state are obviously not ethically possible to
conduct. Animal studies can also test the effects of vitamin A at high
doses, where toxicities are often seen, whereas this type of research
in human populations is also not possible.
A striking feature of vitamin A physiology is the strong mechanism of
homeostatic control of the circulating concentrations of retinol across
a broad range of intake of preformed vitamin A and pro-vitamin A.
Therefore, much of the human observational and experimental work, which
has been carried out within this homeostatically controlled range, may
not be comparable with much of the animal experimental studies done at
levels of deprivation or excess. Also related to the phenomenon of
homeostasis is the limitation of the use of serum retinol levels as a
measure of vitamin A status. Circulating retinol concentrations remain
fairly constant until liver reserves fall to very low levels, below
0.07 µmol/g (17)
, and factors other than intake (especially
infection, malnutrition, and acute stress) can affect circulating
retinol levels, thus limiting the utility of serum levels in other than
long-term prospective studies. Vitamin A status can now be estimated by
the relative dose response and the modified relative dose response
tests that have been widely used to assess vitamin A deficiency states,
but the more precise method of estimating total body stores, the
isotope dilution methods with deuterated retinol (17)
, has not been
widely used because it is technically demanding.
Observational studies have been based generally on estimates of
preformed vitamin A in the diet, with some information from older
studies that reported only total vitamin A, and a small number of
studies related use of vitamin A supplements to cancer risk.
Intervention studies have been conducted with vitamin A doses ranging
from approximately 50–250% of typical total vitamin A dietary
intakes. The period of supplementation has not extended beyond 5 years,
and duration of follow-up has been limited.
|
Cancer-preventive Effects
|
|---|
No consistent association can be found between dietary intake of
preformed vitamin A and risk of lung, gastric, colorectal, skin,
breast, prostate, bladder, or cervical cancer in the reviewed
observational studies (Table 1
).
Intervention studies have shown no beneficial effect of retinol as
compared with placebo on the incidence of basal-cell carcinoma. With
respect to squamous cell carcinoma of the skin, a risk reduction was
found in relatively moderate-risk individuals, but not in high-risk
subjects (18, 19)
. No beneficial effect on gastric cancer was detected
in two intervention studies in China, where retinol was given in
addition to either zinc or a multivitamin preparation (20, 21)
. Data
from a large randomized placebo-controlled trial among North American
smokers and asbestos-exposed workers suggested, if anything, an adverse
effect on lung cancer incidence of a combination of retinol with
ß-carotene (22)
. In one trial in treated lung cancer patients,
supplementation with high-dose retinol was associated with a reduction
in second primary lung cancers (23)
.
The risk of mesothelioma was reduced in an intervention trial among
Australian asbestos miners given retinol as compared with those given
ß-carotene (24)
, but not affected by retinol in combination with
ß-carotene in a North American trial (22)
.
Case-control studies of oesophageal cancer suggested either a modest
direct association with high dietary intake of retinol or no
association. Two Chinese intervention trials did not show a beneficial
effect on oesophageal cancer in which retinol was given in addition to
zinc (20)
or a multivitamin preparation (21)
.
|
Mechanisms of Cancer Prevention
|
|---|
Vitamin A may prevent or delay carcinogenesis at both the
initiation and promotion steps. However, the mechanisms through which
these effects may be exerted have not been fully elucidated. Although
retinol can activate nuclear retinoid receptors via some of its
metabolites, genes involved in chemopreventive actions that are
indirectly regulated by retinol have not been identified. Plausible
mechanisms based on findings in cultured cells and animal models
include modulation of cell properties (cell proliferation,
differentiation, communication, adhesion, migration, and invasion) or
host properties (immune response, angiogenesis). Analysis of these
mechanisms in the context of a chemoprevention trial is required for
validation of their relevance.
|
Evaluation
|
|---|
There is evidence suggesting lack of cancer-preventive
activity of preformed vitamin A for cancers at the following sites in
humans: upper aerodigestive tract, lung, breast (among
post-menopausal women), colorectal, bladder, prostate, and
stomach. There is inadequate evidence with respect to possible
cancer-preventive activity of preformed vitamin A at all other sites
and for second primary cancers of the lung.
Observational studies and randomized controlled trials have been
carried out within the broad range of intakes, which have little or no
effect on the levels of retinol in the circulation (although they may
well have influenced levels of more active metabolites or levels in
other tissues). The results of these studies have been largely
negative, supporting the conclusion that for most cancer sites the
proponderance of evidence does not support a chemopreventive role for
preformed vitamin A. The few randomized, controlled trials conducted to
date likewise do not support the idea that preformed vitamin A has a
substantial chemopreventive role for cancer. There is a suggestion of a
possible benefit of preformed vitamin A against squamous cell skin
cancer among those who have had previous skin cancers, against
mesothelioma among asbestos-exposed workers, and against second primary
lung cancers among those treated for lung cancer. However, the
protective effects for skin cancer and mesothelioma have been seen in
only one of the two published studies for each of these end points, and
there has been only one study of preventing second primary cancers
after lung cancer using very high doses of preformed vitamin A. It is
important to note that all of the previous chemoprevention trials of
vitamin A in humans have been relatively short studies, none extending
beyond 6 years. If vitamin A is protective at earlier stages of
carcinogenesis, as is suggested by some in vitro studies
showing that vitamin A can protect against genetic effects of certain
carcinogens, longer treatment and longer follow-up would be needed to
see preventive effects.
The benefits to health of correcting vitamin A deficiency are clear.
Both animal experimental studies and human studies have shown that
vitamin A deficiency enhances the severity of morbid conditions and
increases total mortality. A limited number of animal studies also
support the hypothesis that vitamin A deficiency increases cancer risk.
Confirmatory studies in vitamin A-deficient populations are lacking.
Two short-term cancer chemoprevention trials conducted among
populations in China with multiple micronutrient insufficiency have
shown no apparent effect of preformed vitamin A on cancer incidence.
The suggestion of potential chemopreventive benefits of high doses of
preformed vitamin A in rat mammary cancer models are encouraging in
that there may be similar benefits for humans, but the fact that these
effects are typically seen only at doses that are toxic or teratogenic
in humans limits enthusiasm for preformed vitamin A as a widely
acceptable cancer chemopreventive agent. Therefore, research is now in
progress to discover more effective and less toxic synthetic retinoids.
This area of inquiry will be covered in volume 4 of this IARC handbook
series.
In summary, there is little evidence to support the idea that within
the wide range bordered by deficiency and toxicity modulating preformed
vitamin A intake has any substantial cancer-preventive effect.
|
Appendix
|
|---|
The meeting participants were W. S. Blaner (Columbia
University, New York, NY), T. Byers, Chairman (University of Colorado,
Denver, CO), J. A. Crowell (National Cancer Institute, Bethesda, MD),
M. I. Dawson (SRI International, CA), S. De Flora (University
of Genoa, Genoa, Italy), N. De Vries (Saint Lucas–Andreas
Hospital, Amsterdam, the Netherlands), L. O. Dragsted (Institute of
Food Safety and Toxicology, Soborg, Denmark), S. Franceschi (Aviano
Cancer Center, PN, Italy), D. J. Hunter (Harvard School of
Public Health and Channing Laboratory, Boston, MA), C. Ijsselmuiden,
(University of Pretoria, Pretoria, South Africa), R. Lotan,
(M. D. Anderson Cancer Center, Houston, TX), R. Mehta (University of
Illinois, Chicago, IL), J. O. Moskaug (University of Oslo,
Oslo, Norway), H. Nau (School of Veterinary Medicine, Hannover,
Germany), P. Nettesheim (National Institute of Environmental Health
Sciences, Research Triangle Park, NC), J. A. Olson (Iowa State
University, Ames, IA), D. I. Thurnham, Vice-Chairman (University of
Ulster, Londonderry, Northern Ireland), H. Tsuda (National Cancer
Center Research Institute, Tokyo, Japan), A. Woodward (Wellington
School of Medicine, Wellington South, New Zealand), R. A. Woutersen
(TNO-Nutrition and Food Research Institute, Zeist, the Netherlands).
The meeting observer was U. Wiegand (Hoffmann-La Roche, Basel,
Switzerland).
|
Acknowledgments
|
|---|
The Foundation for Promotion of Cancer Research Japan, is
gratefully acknowledged for its generous support of the meeting of the
Working Group and the production of the volume of the IARC
Handbooks of Cancer Prevention.
|
Footnotes
|
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported in part by the Foundation for
Promotion of Cancer Research, Japan. 
To whom requests for reprints should be
addressed, at 150 Cours Albert Thomas, 69372 Lyon, Cedex 08, France.
Phone: 33-4-72-73-84-85; Fax: 33-4-72-73-85-75.
Received 6/22/98;
revised 10/ 8/98;
accepted 10/13/98.
|
References
|
|---|
- Sporn M. B., Roberts A. B. Role of retinoids in differentiation and carcinogenesis. Cancer Res, 43: 3034-3040, 1983.[Free Full Text]
- Gudas, L. J., Sporn, M. B., and Roberts, A. B. Cellular biology and biochemistry of retinoids. In: M. B. Sporn, A. B. Roberts, and D. S. Goodman (eds.), The Retinoids. Biology, Chemistry, and Medicine, Ed. 2, pp. 443–519. New York: Raven Press, 1994.
- Mangelsdorf, D. J., Umesono, K., and Evans, R. M. The retinoid receptors. In: M. B. Sporn, A. B. Roberts, and D. S. Goodman (eds.), The Retinoids. Biology, Chemistry, and Medicine, Ed. 2, pp. 319–349. New York: Raven Press, 1994.
- Blomhoff, R. (ed). Vitamin A in Health and Disease, pp.1–677. New York: Marcel Dekker, 1994.
- Kelloff G. J., Boone C. W., Malone W. F., Steele V. E. Chemoprevention clinical trials. Mut. Res, 267: 291-295, 1992.[Medline]
- Davison A., Rousseau E., Dunn B. Putative anticarcinogenic actions of carotenoids: nutritional implications. Can. J. Physiol. Pharmacol, 71: 732-745, 1993.[Medline]
- Perera F. P., Tang D., Grinberg-Funes R. A., Blackwood M. A., Dickey C., Blaner W., Santella R. M. Molecular epidemiology of lung cancer and the modulation of markers of chronic carcinogen exposure by chemopreventive agents. J. Cell. Biochem, 17F: 119-128, 1993.
- Hong, W. K., and Itri, L. M. Retinoids and human cancer. In: M. B. Sporn, A. B. Roberts, and D. S. Goodman (eds.), The Retinoids. Biology, Chemistry, and Medicine, Ed. 2, pp. 597–629. New York: Raven Press, 1994.
- Alberts D. S., Garcia D. J. An overview of clinical cancer chemoprevention studies with emphasis on positive phase III studies. J. Nutr, 125: 692S-697S 1995.
- Lippman S. M., Heyman R. A., Kurie J. M., Benner S. E., Hong W. K. Retinoids and chemoprevention: clinical and basic studies. J. Cell. Biochem. Suppl, 22: 1-10, 1995.
- Kelloff G. J., Crowell J. A., Hawk E. T., Steele V. E., Lubet R. A., Boone C. W., Covey J. M., Doody L. A., Omenn G. S., Greenwald P., Hong W. K., Parkinson D. R., Bagheri D., Baxter G. T., Blunden M., Doeltz M. K., Eisenhauser K. M., Johnson K., Knapp G. G., Longfellow D. G., Malone W. F., Nayfield S. G., Seifried H. E., Swall L. M., Sigman C. C. Strategy and planning for chemopreventive drug development: clinical development plans II. J. Cell. Biochem, 26S: 54-71, 1996.
- Khuri F. R., Kurie J. M., Hong W. K. Multidisciplinary care of lung cancer patients, Part II. Chemoprevention of respiratory tract cancer. Hematol. Oncol. Clin. N. Am. (U. S.), 11: 387-408, 1997.
- Minna J. D., Mangelsdorf D. J. Retinoic acid receptor expression abnormalities in lung cancer: important clues or major obstacles?. J. Natl. Cancer Inst, 89: 602-604, 1997.[Free Full Text]
- Sankaranarayanan R., Mathew B., Varghese C., Sudhakaran P. R., Menon V., Jayadeep A., Nair M. K., Mathews C., Mahalingam T. R., Balaram P., Nair P. P. Chemoprevention of oral leukoplakia with vitamin A and ß carotene: an assessment. Oral Oncol, 33: 231-236, 1997.[Medline]
- Sommer A., West K. P., Jr. Vitamin A Deficiency: Health, Survival, and Vision1-438, Oxford Press New York 1996.
- IARC. Carotenoids. II. Handbooks of Cancer Prevention. Lyon, France: IARC, 1998.
- Olson, J. A. Vitamin A, retinoids, and carotenoids. In: M. E. Shils, J. A. Olson, and M. Shike (eds.), Modern Nutrition in Health and Disease, Ed. 8, pp. 287–307. Philadelphia: Lea and Febiger, 1994.
- Moon T. E., Levine N., Cartmel B., Bangert J. L., Rodney S., Dong Q., Peng Y-M., Alberts D. S., for the Southwest Skin Cancer Prevention Study Group Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Cancer Epidemiol. Biomark. Prev, 6: 949-956, 1997.[Abstract]
- Levine N., Moon T. E., Cartmel B., Bangert J. L., Rodney S., Dong Q., Peng Y-M., Alberts D. S., for the Southwest Skin Cancer Prevention Study Group Trial of retinol and isotretinoin in skin cancer prevention: a randomized, double-blind, controlled trial. Cancer Epidemiol. Biomark. Prev, 6: 957-961, 1997.[Abstract]
- Blot, W. J., Li, J-Y., Taylor, P. R., Guo, W., Dawsey, S., Wang, G-Q., Yang, C. S., Zheng, S-F., Gail, M., Li, G-Y., Yu, Y., Liu, B-Q., Tangrea, J., Sun, L-H., Liu, F., Fraumeni, J. F. Jr., Zhang, Y-H., and Bing, L. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combination, cancer incidence, and disease-specific mortality in the general population. J. Natl Cancer Inst., 85: 1483–1492.
- Li J-Y., Li J-Y., Taylor P. R., Bing L., Dawsey S., Wang G-Q., Ershow A. G., Guo W., Liu Y., Yang, Shen, Q., Wang W., Mark S. D., Zou X-N., Greenwald P., Wu Y-P., Blot W. J. Nutrition Intervention Trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J. Natl. Cancer Inst, 85: 1492-1498, 1993.[Abstract/Free Full Text]
- Omenn G. S., Goodman G. E., Thornquist M. D., Balmes J., Cullen M. R., Glass A., Keogh J. P., Meyskens F. L., Valanis B., Williams J. H., Jr, Barnhart S., Hammar S. Effects of a combination of ß carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med, 334: 1150-1155, 1996.[Abstract/Free Full Text]
- Pastorino U., Infante M., Maioli M., Chiesa G., Buyse M., Firket P., Rosmentz N., Clerici M., Soresi E., Valente M., Belloni P. A., Ravasi G. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J. Clin. Oncol, 11: 1216-1222, 1993.[Abstract/Free Full Text]
- de Klerk, N. H., Musk, A. W., Ambrosini, G. L., Eccles, J. L., Hansen, J., Olsen, N., Watts, V. L., Lund, H. G., Pang, S. C., Beilby, J., and Hobbs, M. S. T. Vitamin A and cancer prevention II: comparison of the effects of retinol and ß-carotene. Int. J. Cancer, 75: 362–367.
This article has been cited by other articles:
|
|
|
|
 
N. van Zandwijk, O. Dalesio, U. Pastorino, N. de Vries, and H. van Tinteren
EUROSCAN, a Randomized Trial of Vitamin A and N-Acetylcysteine in Patients With Head and Neck Cancer or Lung Cancer
J Natl Cancer Inst,
June 21, 2000;
92(12):
977 - 986.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
