9. Recommendations for futu asbestos, tobacco, bidi smoking, betel nut research I chewing, alcohol and environmental toxins influence these systems. The assessment of the literature presented in A better understanding of the way the cell this handbook led to formulation of the following and the body control their vitamin A supply recommendations for future research: will allow better definition of vitamin A status, distribution at times of deficiency, and assess- 1. To study the mechanism of action of ment of effects on how distribution is and its metabolites at the molecular and organized. Epidemiologically, the eye has been genetic levels in relation to carcinogenesis; considered the organ most vulnerable to vitamin A status. However, in the last decade, 2. To identify new nontoxic conjugates and the importance of vitamin A for immune func- formulations of retinol and retinyl esters tion has become apparent. Impaired immune that may show cancer-preventive proper- function has been identified in populations ties; where ophthalmological signs are rare, and morbidity is reduced by vitamin A supple- 3. To consider the conduct of randomized ments. Animal studies have shown that prevention trials of longer duration among vitamin A deficiency increases susceptibility to particularly high-risk groups such as chemical carcinogens. Thus, the aspects of asbestos-exposed individuals and former vitamin A metabolism that are disrupted lung cancer patients; during deficiency should be identified, as should the point at which vitamin A depletion 4. To evaluate exposure biomarkers useful in occurs. Other questions that still need to be epidemiological studies and clinical trials; resolved are how adaptation to low vitamin A intake occurs and what pathway is attenuated S. To continue the follow-up of the terminated or blocked so that vulnerability to experimental intervention trials to assess the long-term carcinogenesis is enhanced. effects of the intervention agents. In some situations, different sources of vita- min A (retinol, and retinyl It is becoming clear that the effects of ) appear to have different effects in vivo retinol metabolites such as the retinoic acids on and comparative experiments should be their nuclear receptors are modulated, either conducted to investigate such observations in directly or indirectly, by other important well, defined experimental models. Concern nuclear receptors and their ligands (glucocorti- Was expressed that combinations of other coids, estrogen, thyroid hormones, vitamin D micro-nutrients with vitamin A, as well as and prostaglandins), other transcription factors foods, might influence retinoid metabolism. and intermediary proteins. The retinoid These factors should also be studied at the signalling system is even more complex in that cellular level and include metabolites that there are at least two classes of retinoid might arise under experimental conditions, receptors and three subtypes of each class that where largé doses are given. in the presence of their ligands can activate or Much current research has been directed to repress retinoic acid responsive elements on explaining how retinol and other retinoids genes. Depending on the dimeric partner and function at the genetic level. Responses of response element, receptors can be affected genes to retinoids controlling cellular differen- differently by their natural or synthetic ligands. tiation and errors in such control can deter- Thus, much remains to be learned on the mole- mine cancer risk. Genetic diversity in human cular mechanisms controlling these processes, populations means that certain genetic the interaction of the different pathophysiolog- polymorphisms within the population may ical factors involved at cellular and tissue levels, predispose to cancer. Individuals who respond and how such environmental factors as positively to increased intake of vitamin A or to

201 IARC Handbooks of Cancer Prevention modifications in retinoid metabolism should 10.2 Overall evaluation be identified. Serum retinol concentrations are h'meostati- It is difficult to evaluate and compare results cally controlled across a wide range of intakes of studies in which protocols differed widely or of both provitamin A carotenoids and in which proper controls and differences in the preformed vitamin A. Research conducted on baseline conditions were neglected, omitted or vitamin A using a wide variety of methods, inadequately described. There is an urgent need from cell cultures in vitro and experimental to develop standard protocols to evaluate the models in animals to observational studies and cancer-preventive properties of retinol and randomized intervention trials in humans retinoids. Standard protocols should specify needs to be evaluated in terms of the overriding continuous quality control of supplements and importance of this system of homeostatic the type of formulation to be used. Such a control. Some research has been done in the strategy should be developed in all studies: setting of vitamin A deficiency, some in the molecular, cellular, animal and human. setting of excess, and some in the wider range Although standardization in human studies is of normal intakes. probably the most difficult, these protocols Observational studies and randomized would help to identify, minimize or quantify controlled trials have been carried out within the variability that undoubtedly exists in the broad range of intakes which have little human studies. or no effect on the levels of retinol in the circultion (although they may well have influ- 10. Evaluation enced levels of more active metabolites in other tissues). The results of these studies have 10.1 Cancer-preventive activity been largely negative, supporting the conclusion 10.1.1 Humans that for most cancer sites the preponderance of There is evidence suggesting lack of cancer-preven- evidence does not support a chemo- tive activity of preformed vitamin A for cancers preventive role for preformed vitamin A. at the following sites: upper aerodigestive tract, The few randomized, controlled trials conducted lung, breast (among postmenopausal women), to date likewise do not support the idea colorectal, bladder, prostate and stomach. that preformed vitamin A has a substantial There is inadequate evidence with respect to chemopreventive role for cancer. There is a possible cancer-preventive activity of pre- suggestion of a possible benefit of preformed formed vitamin A at all other sites and for vitamin A against squamous cell skin cancer second primary cancers of the lung. among those who have had previous skin cancers, and against mesothelioma among 10. 1.2 Experimental animals asbestos-exposed workers, and against second There is limited evidence that retinyl esters have primary lung cancers among those treated for cancer-preventive activity in experimental lung cancer. However, the protective effects animals. This evaluation is based upon consis- for skin cancer and mesothelioma have been tent inhibitory effects in rat mammary cancer seen in only one of the two published studies models, but equivocal effects in mouse mam- for each of these end-points, and there has mary cancer models, and the observation that been only one study of preventing second long-term maintenance of rats on a mixture of primary cancers by preformed vitamin A retinyl acetate and palmitate resulted in an following lung cancer, and this study was increased incidence of mammary gland carci- unusual in that it used very high doses of nomas. In addition, the cancer-preventive preformed vitamin A. It is important to note activity of retinyl esters in other sites and in that all the previous trials of vitamin A chemo- other species was inadequate. prevention in humans has been relatively

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