Pharmacological Uses of Vitamin A Retinoids and Carotenoids Retinoids in Cancer Prevention and Treatment Since the discovery of vitamin A, the observation that the main effects of deficiency are hyperplasia and loss of differentiation of squamous epithelium has raised speculation that the vitamin may be associated with carcinogenesis. Either deficiency may be a risk factor for cancer or increased intake may be protective. Deficient animals develop more spontaneous tumors and are more sensitive to chemical carcinogens, whereas liver reserves of vitamin A are lower in patients with cancer than in controls. One of the genes repressed by retinoic acid is the myc-oncogene.

The addition of relatively high concentrations of retinol to organ culture media produces changes that are apparently the opposite of those seen in deficiency; chick epidermis, which is normally keratinized, becomes mucus producing and in some cases ciliated. Studies of experimentally induced and transplanted tumors in experimental animals given very high intakes of retinol or retinoic acid, and of tumors in tissue culture with very high concentrations of retinol and retinoic acid, suggest that there is a potentially beneficial effect of very high intakes in inhibiting the initiation and growth of epithelial tumors.

The doses of retinol that are protective in animals are in the toxic range (Section 2.5.1) and are unlikely to be useful in cancer therapy or prevention. A number of synthetic retinoids have been developed, in a searchfor compounds that show anticancer activity, but are metabolized, stored, and transported differently, or bind to different subtypes of retinoid receptor and are less toxic. RXR-selective ligands are less toxic and more active in animal cancer models than RAR ligands (Lippman and Lotan, 2000). Fenretinamide, and possibly other retinoids that have antitumor activity, exerts at least part of its action by induction of apoptosis by a receptor-independent mechanism (Wu et al., 2001).

In addition to the regression of established tumors, a number of retinoids show apparent inhibition of the chemical induction of the bladder and other epithelial tumors in experimental animals. The effect is not in fact inhibition of carcinogenesis, but rather a lengthening of the latent period between the initiation step of carcinogenesis and the development of tumors. Although perhaps not as exciting as compounds that prevent the development of cancers, such a delaying action may be useful. If the results can be scaled from experimental animals to man, then it seems that the recurrence of bladder tumors after initial surgery or chemotherapy might be delayed by 5 to 10 years, a clinically useful effect (Hicks and Turton, 1986). Retinoids in Dermatology 13-Q's-retinoic acid (isotretinoin, Accutane®) is used orally, and all-frans-retinoic acid (Tretinoin®) topically, for treatment of severely disfiguring cystic acne. Etretinate (the trimethoxyphenyl analog of retinoic acid) and tazarotene (a receptor-specific retinoid) are used topically for the treatment of psoriasis. They are effective in cases in which other therapy has failed, and at lower levels than are required for the control of tumor development in experimental animals, although they have been associated with birth defects (Section; Johnson and Chandraratna, 1999). Carotene Average daily intakes of carotenoids in western countries are of the order of 7 to 8 mg per day: a-carotene, 0.7 mg; f-carotene, 3 mg; lutein and zeaxanthin, 2.5 mg each; and lycopene, 1 mg. The major importance of dietary carotenoids is as precursors of vitamin A; even among omnivores in western countries, some 25% to 30% of vitamin A is provided by carotenes rather than preformed retinol. In plants and microorganisms, carotenoids function not only as pigments (e.g., in flowers), but also as energy-transferring molecules in photosynthesis, broadening the spectrum of light that can activate chlorophyll. A number of carotenoids of natural origin are used as food colors - those that have an unsubstituted f -ionone ring will also have provitamin A activity.

Most carotenoids are stored in adipose tissue. Lutein and zeaxanthin (but not other carotenoids) are specifically accumulated in the pigment layer of the retina, and there is epidemiological evidence that they are protective against the development of age-related macular degeneration. There is also epidemi-ological evidence that lutein and zeaxanthin may provide protection against the development of cataracts. Lycopene is accumulated in the adrenal glands and testes at concentrations 20-fold higher than occur in adipose tissue, suggesting that there is active accumulation in these two tissues. Epidemiological evidence suggests that it may be protective against prostate cancer (Stahl and Sies, 1996; Gannetal., 1999; Handelman, 2001).

In addition to their importance as precursors of vitamin A, carotenes can also act, at least in vitro (and under conditions of low oxygen tension), as antioxidants, trapping singlet oxygen generated by photochemical reactions or lipid peroxidation of membranes (Burton and Ingold, 1984). Studies with p-carotene and other carotenoids have not shown any consistent effect on in vivo markers of oxidative damage (Institute of Medicine, 2000).

Epidemiological and case-control studies show a negative association between p - carotene intake and a number of cancers (Peto et al., 1981), suggesting that p-carotene may have a protective effect against some forms of cancer, and hence a function in its own right, not simply as a precursor of retinol. This has generally been assumed to be due to the antioxidant activity of p-carotene, although it is noteworthy that different dietary carotenoids induce different isoenzymes of cytochrome P450 and might be predicted to have positive or negative effects on (chemical) carcinogenesis (Jewell and O'Brien, 1999). In addition, there is evidence that some carotenoids may have a genomic action in their own right, inducing synthesis of connexin 43, one of the proteins involved in maintaining tissue integrity and cell-to-cell communication. Teicher and coworkers (1999) reported that the action of apo-carotenoic acids is to increase the stability of connexin mRNA (by binding to the 3'-untranslated region), rather than enhancement of gene expression. Increased synthesis of connexin might retard the growth of a tumor by maintaining an outer layer of tightly connected normal cells or stimulating intercell gap-junction communication (Stahl and Sies, 1996; Bertram, 1999; Stahl et al., 2000).

On the basis of the epidemiological evidence, there have been a number of intervention studies using supplements of p-carotene. They have typically used supplements of 20 to 30 mg per day p-carotene in a highly available form, compared with average intakes from foods of 7 to 8 mg of mixed carotenoids of generally low biological availability. In the Linxian study in China (Blot et al., 1993), supplements of p-carotene, vitamin E, and selenium to a marginally malnourished population led to a reduction in mortality from a variety of cancers, especially gastric cancer. The Physicians' Health Study (Hennekens et al., 1996) was a 12-year trial in the United States in which p-carotene supplements showed no effect on the incidence of cardiovascular disease or cancer.

Two major intervention trials among people at risk of lung cancer were the Alpha-Tocopherol Beta-Carotene Study in Finland, in which heavy smokers were given supplements of 20 mg per day of p-carotene and/or 50 mg of vitamin E (Alpha-Tocopherol Beta-Carotene Cancer Prevention Study Group, 1994), and the CARET Study (Carotene and Retinol Efficacy Lung Cancer Chemoprevention Trial; Omenn et al., 1996a, 1996b) in the United States involving people who had been exposed to asbestos dust, who received 30 mg of p-carotene and 7,500 [g of retinyl palmitate per day. Both studies showed a significant increase in death from lung cancer among people taking the supposedly protective carotene supplements. A number of hypotheses have been advanced to explain this unexpected finding:

1. The studies were performed on established heavy smokers and people who had been exposed to asbestos dust some years previously. It has been suggested that whereas p-carotene may inhibit induction of cancers by reactive oxygen species, it may also enhance later stages in tumor development.

2. The plasma concentrations of p-carotene in the intervention trials were considerably higher than those observed to be protective in epidemio-logical studies; as with any antioxidant, p-carotene is also potentially a prooxidant. This is especially likely in the lung, where thepartialpressure of oxygen is high; the radical-trapping antioxidant action is observed at low partial pressures of oxygen (Burton and Ingold, 1984). Whereas p-carotene may be an antioxidant at low levels of intake, higher intakes may lead to the formation of oxidized metabolites that are prooxidants (Wang and Russell, 1999; Young and Lowe, 2001).

3. It is possible that whereas asymmetric cleavage of p-carotene at low concentrations leads to the formation of apocarotenals that can be oxidized to retinoic acid (Section, at higher levels apocarotenals and apocarotenoic acids may antagonize retinoic acid. Ferrets (which metabolize carotene similarly to human beings) show lower concentrations of retinoic acid in the lung when they are given high intakes of p-carotene, as well as lower expression of RARp, although RARa and RARy are unaffected. In lung cancer cells in vitro, RARp has tumor-suppressing activity (Houle et al., 1993).

4. What the epidemiological studies have actually shown is a negative association between various types of cancer and the consumption of fruits and vegetables that are rich in carotenoids and a great many other potentially protective compounds (Section 14.7). It may be that p-carotene is simply a marker for some other protective factor.


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