Retinoids differential therapy

Chomienne, C., Fenaux, P., and Degos, L. (1996) Retinoid differentiation therapy in promyelocytic leukemia, FASEB J. 10, 1025-1030. 

There has been some concern expressed regarding the use of CSFs to treat MDS patients. Because these cytokines have proliferative activity, they have the potential to induce a leukaemic transformation in the malignant clone. However, the combined use of CSFs with cytotoxic drugs such as cytosine arabinoside (ara-C) appears promising. If leukaemic clones are induced to proliferate by the cytokine, then they are killed by ara-C as they enter the cell cycle. Other forms of differentiation therapy, such as treatment with retinoids, 1,25-dihydroxyvitamin D3 and interferons, have also been tested, but results have been variable. 

Chao W, Rudd CJ, Costa E, Jong L, Hobbs PD, Lehmann JM, Pfahl M, Lombardo A, Ely KA, Quick T et al (1995) Effects of receptor-selective retinoids on epidermal cells in the presence of the tumor promoter 12-0-tetradecanoylphorbol-13-acetate. American Association of Cancer Research Special Conference, Mechanism of Action of Retinoids, Vitamin D and Steroid Hormones. Whistler, British Columbia, Canada Bollag W, Apfel C, LeMotte P (1995) Retinoids Achievements, prospectives and future goals. In S Waxman (ed.) Challenges in Modem Medicine, VoL 10. Proceedings of the 6th Conference on Differentiation Therapy. Ares Serono Symposia Publications, Rome, 285-302... 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

The UV radiation causes premature skin aging. This photo-aging is characterized by wrinkles, mottled pigmentation, dry and rough skin, and loss of skin tone. Use of topical vitamin A derivatives like tretinoin can improve photo-aged skin mainly by changing epidermal differentiation.52 However, skin dryness does not improve and even worsens with retinoid therapy, as well known from its systemic and topical use in several diseases in clinical dermatology. 

Retinoids Retinoids are compounds derived from R. or its synthetic analogues but which do not exhibit any vitamin A activity. Some of them have inhibitory effects on cell growth and differentiation and are used in therapy for acne (e.g., motretinide) and psoriasis (etretinate) . 

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