Receptors retinoid

Agents which enhance the host s response against neoplasias or force them to differentiate are termed biological response modifiers. Examples include interleukin 2 which is used to treat renal cell carcinoma, interferon a which is active against hematologic neoplasias, and tretinoin (all-trans retinoic acid) which is a powerful inducer of differentiation in certain leukemia cells by acting on retinoid receptors. Side effects include influenza like symptoms, changes in blood pressure and edema. 

The known beneficial effects of retinoids on malignancies are assumed to relate to retinoid receptor-mediated antipromoting and anti-initiating effects. The latter appeals to be influenced by interference of several xenobiotics with different steps of the retinoid metabolism in the target cell. Of the carotenoids, (3-carotene is the most potent retinol precursor, yet being... 

Synthetic Retinoid Receptor Selective Agonists/ Antagonists... 

The concept of drug development is based on the findings that retinoid receptors (RARs and RXRs) offer a new approach by targeting different genes depending on the activated retinoid receptor complexes. The multiplicity of these retinoid signaling pathways affords potential for therapeutic opportunity as well as retinoid therapy associated undesired side effects. It is possible that the indiscriminate activation of all pathways by nonspecific retinoid ligands could lead to unacceptable side effects so that any enhanced efficacy would be obtained at the cost of enhanced toxicity. 

Adapalene (Table 1), a new highly stable naphtoic acid arotinoid with lipophilic properties, does not bind to CRABP, although it enhances its synthesis, and its rank-order of retinoid receptor affinity apears to be RAR(3 > RARy > > RARa. 

Wei LN (2003) Retinoid receptors and their coregulators. Annu Rev Pharmacol Toxicol 43 47-72... 

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... 

Retinoids (i.e., tretinoin and tazarotene) mediate cellular responses primarily through activation of nuclear retinoid receptors [rr]. There are two types of nuclear retinoic acid receptors the retinoic acid receptors (RARs) and the retinoid X receptors. Each type of receptor contains three receptor subtypes alpha, beta, and gamma [rr, 11]. Among the commonly prescribed retinoids, tretinoin activates the RARs alpha, beta, and gamma directly, and the retinoid X receptors indirectly (through conversion of tretinoin to 9-cis-retinoic acid) [rr, 13]. Conversely,... 

A most important function of vitamin A is in the control of cell differentiation and mrnover. PsA-trans-retinoic acid and 9-cw-retinoic acid (Figure 45-1) regulate growth, development, and tissue differentiation they have different actions in different tissues. Like the steroid hormones and vitamin D, retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes. There are two families of nuclear retinoid receptors the retinoic acid receptors (RARs) bind all-rrijw-retinoic acid or 9-c -retinoic acid, and the retinoid X receptors (RXRs) bind 9-cw-retinoic acid. 

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... 

Klaholz, BP and D Moras. 1998. A structural view of ligand binding to the retinoid receptors. Pure Appl Chem 70(1) 41—47. 

Retinoids play a role in the regulation of differentiation and development. This they achieve by binding to retinoid receptor-proteins in the nucleus and inhibiting the expression of transcription factors that regulate proliferation. Hence, deficiency of vitamin A can result in impaired differentiation and hence foetal malformation and spon-... 

Bexarotene is a member of a subclass of retinoids that selectively activate rehnoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of rehnoic acid receptors (RARs). After oral administration bexarotene is rapidly absorbed. Bexarotene is thought to be eliminated primarily through the hepatobiliary system. It is approved for the treatment of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. Adverse events possibly related to treatment are lipid abnormalities, hypothyroidism, rash, and blood dyscrasias. 

Like other retinoids, tazarotene (Razorac) acts by binding to RARs and altering gene expression. Tazarotene appears to be particularly selective for the retinoid receptors RAR-(3 and RAR-y,but the clinical significance of this observation is unknown. 

Alitretinoin (Panretin) is a naturally occurring endogenous retinoid that binds to and activates all known retinoid receptors (both RARs and RXRs). It is approved for the topical treatment of cutaneous lesions of Kaposi s sarcoma. Most patients have local irritation while using alitretinoin gel however, the irritation rarely necessitates discontinuation of therapy. 

Retinoid Hormones Retinoids are potent hormones that regulate the growth, survival, and differentiation of cells via nuclear retinoid receptors. The prohormone retinol is synthesized from vitamin A, primarily in liver (see Fig. 10-21), and many tissues convert retinol to the hormone retinoic acid (RA). 

All tissues are retinoid targets, as all cell types have at least one form of nuclear retinoid receptor. In adults, the most significant targets include cornea, skin, epithelia of the lungs and trachea, and the immune system. RA regulates the synthesis of proteins essential for growth or differentiation. Excessive vitamin A can cause birth defects, and pregnant women are advised not to use the retinoid creams that have been developed for treatment of severe acne. 

Vitamin A absorbs UV light between 300 and 350 nm. After acute exposure to UVA or UVB a dose-dependent decrease of vitamin A was shown in mouse59 and humans.84 UV irradiation markedly reduced mRNA and protein of the nuclear retinoid receptors RARy and RXRa in humans and led to a near loss of retinoic acid induction of the RAR/RXR target genes and the cellular retinoic acid binding protein II thus effectively causing additionally a functional vitamin A deficiency.85... 

Mangelsdorf DJ, Umesono K, Evans RM The retinoid receptors, in Sporn MB, Roberts AB, Goodman DS (eds) The Retinoids, Biology, Chemistry and Medicine. 2nd ed. Raven Press, New York, 1994, pp. 319-350. 

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