Retinoids, in cancer chemoprevention

Considerable interest has focused on the possibility that vitamin A and other retinoids may find important roles in cancer chemoprevention and therapy (Marcus and Coulson, 1996). 

Freemanfle, S.J., Spinella, M.J. and Dmitrovsky, E. (2003) Retinoids in cancer therapy and chemoprevention promise meets resistance. Oncogene, 22, 7305-7315. 

The use of synthetic retinoids in cancer prevention and therapy for both cutaneous and internal tumors is potentially the most significant clinical use of these drugs, requiring further investigation and clarification. Based on the results of preliminary studies, it appears that chronic maintenance therapy is needed for successful chemoprevention of cancer with retinoids. One must now conclude that the future of the retinoids is most promising, particularly with the continuing development of new synthetic compounds that may improve still further their efficacy or tolerability. 

De Palo G, Formelli F (1995) Risks and benefits of retinoids in the chemoprevention of cancer. Drug Safety 13 245-256... 

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

Abu J, Batuwangala M, Herbert K et al (2005) Retinoic acid and retinoid receptors potential chemopreventive and therapeutic role in cervical cancer. Lancet Oncol 6 712-720... 

Sun SY and Lotan R (2002) Retinoids and their receptors in cancer development and chemoprevention. Critical Reviews in Oncology and Haematology 41,41-55. 

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 Evaluated for Chemopreventive Activity against Mammary Cancer Induced in Rats by Methyinitrosourea... 

Using the MNU mammary tumor system. Moon et al. (1983a) have evaluated a number of synthetic retinoids for prevention of mammary cancer (Table II). All the active compounds listed in Table II are highly effective in reducing the incidence and number of mammary cancers. 4-Hydroxyphenylretinamide (4-HPR) (El6) is the most efficacious synthetic retinoid in mammary cancer prevention when both chemopreventive activity and toxicity are taken into consideration. 

Retinoids Evaiuated for Chemopreventive Activity against Urinary Biadder Cancer in Rats and/or Mice"... 

Finally, chemoprevention with systemic retinoids has demonstrated promise in decreasing the incidence of new primary non-melanoma skin cancers (NMSCs) in immxmocompromised post-transplantation recipients. However, there is limited evidence for the use of systemic retinoids in the non-transplantation patients at high risk for NMSC. This study was designed as prospective, randomised, double-blind, placebo-controlled clinical trial [3. ... 

Delescluse C, Cavey MT, Martin B, Bernard BA, Reichert U, Maignan J, Darmon M, Shroot B (1991) Selective high affinity retinoic acid receptor a or p-y ligands. Mol Pharmacol 40 556-562 Spom MB, Newton DL (1979) Chemoprevention of cancer with retinoids. Fed Proc 38 2528-2534 Newton DL, Henderson WR, Spom MB (1980) Stmcture-activity relationships of retinoids in hamster tracheal organ culture. Cancer Res 40 3413-3425... 

McCormick DL, Moon RC (1986) Retinoid-tamoxifen interaction in mammry cancer chemoprevention. Carcinogenesis 1 193-196... 

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