Retinoid in cancer

Upregulation of retinoid receptor expression and function by provitamin A carotenoids may play a role in mediating the growth inhibitory effects of retinoids in cancer cells (Lian et al. 2006, Prakash et al. 2004). However, it is unclear if non-provitamin A carotenoids and their metabolites may act... 

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. 

Introduction.—This Report covers the literature published up to approximately the end of September, 1981. Few new carotenoid structures have been reported. The main advances in carotenoid chemistry have been in the stereospecific synthesis of carotenoids with chiral end-groups. Current interest in the possible use of retinoids in cancer chemotherapy has prompted the preparation of a considerable number of retinoic acid analogues. There has been no major new development in the use of physical methods but h.p.l.c. becomes more and more the method of choice for carotenoid separation, purification, and assay, and the increasing number of papers on resonance Raman spectroscopy emphasizes the potential value of this technique in the carotenoid field. 

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

One of the most exciting potential uses for the retinoids lies in the area of cancer prevention. The rationale for the use of retinoids in cancer prevention derives from their ability to control normal differentiation in many epithelial tissues. Animal studies that document the efficacy of retinoids in cancer prevention have been reviewed in detail earlier in this chapter. To date, clinical trials have concentrated primarily on the reversal of premalignant conditions or the prevention of recurrent lesions in patients with certain malignant diagnoses. 

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. 

Smith MA, Parkinson DR, Cheson BD, Friedman MA (1992) Retinoids in cancer therapy. J Clin Oncol 10 839-864... 

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. 

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. 

Pasquali, D, V Rossi, G Bellastella, A Ballastella, and AA Sinisi. 2006. Natural and synthetic retinoids in prostate cancer. Curr Pharm Des 12 1923-1929. 

Platinum complexes are cytotoxic agents yet the paradigm in cancer chemotherapy has moved to a more targeted approach, with special emphasis on signaling pathways. In this respect a remarkable story is that of arsenic trioxide, As203 (Trisenox, Cell Therapeutics Inc, Seattle, USA) which was approved by the FDA in September 2000 for treatment of acute promomyelo-cytic leukemia (APL) in patients who have relapsed or are refractory to retinoid and anthracycline chemotherapy. An estimated 1,500 new cases of APL are diagnosed yearly in the US, of which an... 

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). 

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). 

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

In normal cells, the erqjression of RARs is enhanced by retinoids. Many cancer cells lose the ability to respond to retinoids because they lack COUP-TF (a mammalian ecdysone-like transcription factor). Expression of COUP-TF in cancer cells can restore the retinoid response. Apparently, COUP-TF is required for the interaction of the RARs with the transcriptional co-activator CBP, enhancing DNA binding. ... 

Kelly WK, Osman I, Reuter VE, Curley T, Heston WD, Nanus DM, Scher HI. The development of biologic end points in patients treated with differentiation agents an experience of retinoids in prostate cancer. Qin Cancer Res 2000 6(3) 838. ... 

---