Retinoids in Cancer Prevention and Treatment

1 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 he 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 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 search for 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 mmors. Although perhaps not as exciting as compounds that prevent the development of cancers, such a delaying action may be usefitl. If the results can be scaled from 

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Niles RM. Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. Nutrition 2000 16 1084-9. 

Blanchet-Bardon C, Nazzaro V, Rognin C, Geiger J-M, Puissant A (1991) Acitretin in the treatment of severe disorders of keratinization. Results of an open study. J Am Acad Dermatol 24 982-986 Bollag W, Holdener EE (1992) Retinoids in cancer prevention and therapy. Ann Oncol 3 513-526 Bonhonune L, Fredj G, Ecstein E, Maurisson G, Farabas C, Misset JL, Jasmin C (1994) Treatment of AIDS-associated Kaposi s sarcoma with oral tretinoin. Am J Hosp Pharm 51 2417-2419. 

Clinical studies in the use of retinoic add for the treatment or chemoprevention of cancers are becoming more common. Of particular interest has been the use of natural retinoids for the treatment of APL [101,102,193,194,236-241], also called acute non-lymphocytic leukaemia type M3 (ANLL-M3) and French-American-British criteria for M3 leukaemia (FAB M3). The incidence of reports of attainment of complete remissions in patients treated with RA has dramatically increased over the past few years. The following paragraphs describe some of the results obtained to date. Lastly, a brief summary of other studies on the effect of RA in cancer prevention/treatment will be given. 

Retinoids have also been studied for their potential in the treatment of oral leucoplakia [243], the prevention of cancers [244,245], and in the treatment of a leukaemia other than APL [246]. In one study, 13-c/s-retinoic acid was found effective for treatment of oral leucoplakia with 16 out of 24 patients responding positively to the treatment [243]. An average of 63% reduction of skin cancers was observed in 5 patients treated with 13-cis-RA (2 mg/kg daily) over a period of 2 years [244]. After discontinuance of therapy, tumour incidence increased 8.5-fold relative to the frequency during treatment. Similarily, 13-ew-RA treatment at 50-100 mg m day was effective in the prevention of second primary tumours in patients with squamous-cell carcinoma of the head and neck [245], although the retinoid was ineffective in preventing recurrences of the original tumour. Recently, the first effective response to oral RA therapy from a patient with a blast crisis of chronic myelogenous leukaemia (CML-BC) was reported [246]. 

Careful analysis of structure-function relationships may lead to the synthesis of newer retinoids with a superior therapeutic index that may be more suitable for cancer prophylaxis in healthy patients. Nevertheless, ongoing trials in cancer treatment and prevention with currently available retinoids will provide valuable... 

Kraemer KH, Di Giovanna JJ, Moshell AN, Tarone RE, Peck GL (1988) Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 318 1633-1637 Krueger GG, Drake LA, Elias PM, Lowe NJ, Guzzo C, Weinstein GD, Lew-Kaya DA, Lue JC, Sefton J, Chandraratna RA (1998) The safety and efficacy of tazarotene gel, a topical acetylenic retinoid, in the treatment of psoriasis. Arch Dermatol 134 57-60... 

In foods retinol is accompanied by a number of analogues and metabohtes, differing in the ionone cycle or side chain structures. Freshwater fish contain, for example, 3,4-didehydroretinol known as vitamin Kj (5-2), which has about 40% of the activity of retinol. Marine fish, birds and mammals do not synthesise this vitamin. Synthetic derivatives related chemically to vitamin A are collectively called retinoids. These substances are used for the treatment of various skin conditions, such as severe acne, sun spots, wrinkles and psoriasis. Some retinoids may even help treat or prevent certain forms of skin cancer. 

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