関: specific agents

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/06/28 12:14:00」(JST)

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1st, 2nd, 3rd-generation retinoid compounds

The retinoids are a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth.

Retinoids have many important and diverse functions throughout the body including roles in vision, regulation of cell proliferation and differentiation, growth of bone tissue, immune function, and activation of tumor suppressor genes.

Research is also being done into their ability to treat skin cancers. Currently 9-cis retinoic acid may be used topically to help treat skin lesions from Kaposi's sarcoma.

Types

There are three generations of retinoids:

First generation retinoids: which include retinol, retinal, tretinoin (retinoic acid, Retin-A), isotretinoin, and alitretinoin.
Second generation retinoids: which include etretinate and its metabolite acitretin.
Third generation retinoids: which include tazarotene, bexarotene and Adapalene.

Some authors consider retinoids derived from pyranones as the fourth generation. One such compound is Seletinoid G.^[1]

Structure

The basic structure of the hydrophobic retinoid molecule consists of a cyclic end group, a polyene side chain and a polar end group. The conjugated system formed by alternating C=C double bonds in the polyene side chain are responsible for the color of retinoids (typically yellow, orange, or red). Hence, many retinoids are chromophores. Alternation of side chains and end groups creates the various classes of retinoids.

First and Second generation retinoids are able to bind with several retinoid receptors due to the flexibility imparted by their alternating single and double bonds.

Third generation retinoids are less flexible than First and Second generation retinoids and therefore, interact with fewer retinoid receptors.

Absorption

The major source of retinoids from the diet are plant pigments such as carotenes and retinyl esters derived from animal sources. Retinyl esters are hydrolyzed in the intestinal lumen to yield free retinol and the corresponding fatty acid (i.e. palmitate or stearate). After hydrolysis, retinol is taken up by the enterocytes. Retinyl ester hydrolysis requires the presence of bile salts that serve to solubilize the retinyl esters in mixed micelles and to activate the hydrolyzing enzymes ^[2]

Several enzymes that are present in the intestinal lumen may be involved in the hydrolysis of dietary retinyl esters. Cholesterol esterase is secreted into the intestinal lumen from the pancreas and has been shown, in vitro, to display retinyl ester hydrolase activity. In addition, a retinyl ester hydrolase that is intrinsic to the brush-border membrane of the small intestine has been characterized in the rat as well as in the human. The different hydrolyzing enzymes are activated by different types of bile salts and have distinct substrate specificities. For example, whereas the pancreatic estrase is selective for short-chain retinyl esters, the brush-border membrane enzyme preferentially hydrolyzes retinyl esters containing a long-chain fatty acid such as palmitate or stearate. Retinol enters the absorptive cells of the small intestine, preferentially in the all-trans-retinol form.

Uses

Retinoids are used in the treatment of many diverse diseases and are effective in the treatment of a number of dermatological conditions such as inflammatory skin disorders,^{[citation needed]} skin cancers,^{[citation needed]} disorders of increased cell turnover (e.g. psoriasis),^[3] photoaging,^[4] and skin wrinkles ^[5]

Common skin conditions treated by retinoids include acne and psoriasis.^[6]

Isotretinoin is not only considered the only known possible cure of acne in some patients, but was originally a chemotherapy treatment for certain cancers, such as leukemia.

Human embryonic stem cells also more readily differentiate into cortical stem cells in the presence of retinoids^[7]

Retinoids are known to reduce the risk of head and neck cancers.^[8]^[9]

Synthesis

Retinoids can be synthesized in a variety of ways. A common procedure to lower retinoid toxicity and improve retinoid activity is glucuronidation. Walker et al. have proposed a novel synthesis to accomplish glucuronidation.^[10]

Toxicity

Toxic effects occur with prolonged high intake. The specific toxicity is related to exposure time and the exposure concentration. A medical sign of chronic poisoning is the presence of painful tender swellings on the long bones. Anorexia, skin lesions, hair loss, hepatosplenomegaly, papilloedema, bleeding, general malaise, pseudotumor cerebri, and death may also occur.^{[medical citation needed]}

Chronic overdose also causes an increased lability of biological membranes and of the outer layer of the skin to peel.^[11]

Recent research^{[citation needed]} has suggested a role for retinoids in cutaneous adverse effects for a variety of drugs including the antimalarial drug proguanil. It is proposed that drugs such as proguanil act to disrupt retinoid homeostasis.

Systemic retinoids (isotretinoin, etretinate) are contraindicated during pregnancy as they may cause CNS, cranio-facial, cardiovascular and other defects.

References

^ Mukherjee, S; Date, A; Patravale, V; Korting, HC; Roeder, A; Weindl, G (2006). "Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety.". Clinical interventions in aging 1 (4): 327–48. doi:10.2147/ciia.2006.1.4.327. PMID 18046911.
^ Noy, N. (2006) "Vitamin A", "Biochemical, Physiological, & Molecular Aspects of Human Nutrition", M. H. Stipanuk 2nd Ed.
^ http://www.mayoclinic.org/diseases-conditions/psoriasis/basics/treatment/con-20030838
^ Stefanaki C, Stratigos A, Katsambas A (June 2005). "Topical retinoids in the treatment of photoaging". J Cosmet Dermatol 4 (2): 130–4. doi:10.1111/j.1473-2165.2005.40215.x. PMID 17166212.
^ "Improvement of naturally aged skin with vitamin A (retinol)". Arch Dermatol 143: 606–12. 2007. doi:10.1001/archderm.143.5.606. PMID 17515510.
^ National Psoriasis Foundation
^ http://www.nature.com/neuro/journal/vaop/ncurrent/fig_tab/nn.3041_F1.html Archived November 5, 2014, at the Wayback Machine.
^ Smith, W; Saba, N (2005). "Retinoids as chemoprevention for head and neck cancer: Where do we go from here?". Critical reviews in oncology/hematology 55 (2): 143–52. doi:10.1016/j.critrevonc.2005.02.003. PMID 15886010.
^ 2009 Internal Medicine Boards-Style Q&A, Q:378, p.232; A:378, p.125
^ Walker, JR; Alshafie, G; Abou-Issa, H; Curley Jr, RW (2002). "An improved synthesis of the C-linked glucuronide of N-(4-hydroxyphenyl)retinamide". Bioorganic & Medicinal Chemistry Letters 12 (17): 2447–50. doi:10.1016/s0960-894x(02)00427-4. PMID 12161154.
^ New Zealand Dermatological Society

The Pharmacological Basis of Therapeutics, 10th Edition, Goodman & Gilman.
Clinical Pharmacology, P.N. Bennett & M.J. Brown.

External links

Retinoids at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. 尋常性ざ瘡の治療 treatment of acne vulgaris
2. 分化（レチノイン酸）症候群 differentiation retinoic acid syndrome
3. 成人における急性前骨髄球性白血病の初期治療 initial treatment of acute promyelocytic leukemia in adults
4. 光による老化 photoaging
5. 再発性および難治性の急性前骨髄球性白血病の治療 treatment of relapsed or refractory acute promyelocytic leukemia in adults

English Journal

Novel treatment of acute promyelocytic leukemia: As₂O₃, retinoic acid and retinoid pharmacology.

Zhu G, Mische SE, Seigneres B1.Author information 1Institute of Oncology of George Zhu, 422407, Beijing, China. sansan4240732@163.com.AbstractAcute promyelocytic leukemia(APL), a specific characteristic of t(15;17) chromosome translocation, represents 5% to 15% of cases of acute nonlymphocytic leukemia. An alternative approach is to consider retinoic acid(all-trans RA, ATRA or 13-cis RA or 9-cis RA) plus chemotherapy or RA plus As₂O₃ regimens as now novel therapy. Molecular gene analyses are conclusive in vivo evidence that oncogenic PML/RARa plays a crucial role in APL leukemogenesis. As a novel approach to APL treatment, one possible the action of RA, A consense sequence (5'-TCAGGTCATGACCTGA-3') has been postulated for the thyroid hormone (TRE) and retinoic acid responsive element (RARE) containing half palindromes, which located in the promoter region of target genes. High dose (100-fold) of RA-RARE-PML/RARa complex in intracellular localization appears to relieve repressor from DNA binding, including corepressors N-CoR, SMRT and HDACs, release PML/RARa- mediated transcriptional repression, and release histone deacetylase activity from PMLRARa. The resulting PML/RARa oncoprotein proteolytic degradation through the autophagy-lysosome pathway and the ubiquitin SUMO-proteasome system (UPS), as well as caspase 3 (cleavage site Asp522 within a-helics region of PML component of the fusion protein) or neutrophil elastase, or lysosomal protease enzyme induction. PML protein relocalizes into the wild-type nuclear body (PML-NB) configuration or/and wild-type RARa upregulated. An effect to relieve the blockade (inhibition) of PML/RARA-mediated RA dependent promyelocytic differentiation, and retinoic acid in APL therapy (see Figure in the full text, George Zhu, 1991). Here, like v-erbA, PML/RARa is a (strong) transcriptional repressor of the RA receptor (RAR) complex, and PML/RARa fusion receptor gene act as conditional oncogenic receptor (translocated chimeric retinoic acid a signaling) or oncogenic PML/RARa may participate in leukemogenesis of APL through blocking RA-mediated promyelocytic differentiation. This is first described in eukaryotes.
Current pharmaceutical biotechnology.Curr Pharm Biotechnol.2014 Oct;14(9):849-58.
Acute promyelocytic leukemia(APL), a specific characteristic of t(15;17) chromosome translocation, represents 5% to 15% of cases of acute nonlymphocytic leukemia. An alternative approach is to consider retinoic acid(all-trans RA, ATRA or 13-cis RA or 9-cis RA) plus chemotherapy or RA plus As₂O₃
PMID 24433507

An N-terminal splice variant of human Stat5a that interacts with different transcription factors is the dominant form expressed in invasive ductal carcinoma.

Tan D1, Chen KE2, Deng C3, Tang P4, Huang J4, Mansour T2, Luben RA3, Walker AM5.Author information 1Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521-0121, United States; College of Medicine/Institute of Medical Sciences, Jishou University, Jishou 416000, Hunan, PR China.2Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521-0121, United States.3Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521-0121, United States; Department of Biochemistry, University of California, Riverside, Riverside, CA 92521-0121, United States.4People's Hospital of Xiangxi Autonomous Region, Jishou University, Jishou 416000, Hunan, PR China.5Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521-0121, United States. Electronic address: ameae.walker@ucr.edu.AbstractWe have identified a new variant of human Stat5a, found at higher ratios to full-length Stat5a in invasive ductal carcinoma versus contiguous normal tissue. The variant, missing exon 5, inhibits p21 and Bax production and increases cell number. After prolactin stimulation, only full-length Stat5a interacts with the vitamin D and retinoid X receptors, whereas only Δ5 Stat5a interacts with activating protein 1-2 and specificity protein 1. Prolactin also oppositely regulates interaction of the two Stat5a forms with β-catenin. We propose that a change in splicing leading to upregulation of this new isoform is a pathogenic aspect of invasive ductal carcinoma.
Cancer letters.Cancer Lett.2014 Apr 28;346(1):148-57. doi: 10.1016/j.canlet.2013.12.030. Epub 2013 Dec 30.
We have identified a new variant of human Stat5a, found at higher ratios to full-length Stat5a in invasive ductal carcinoma versus contiguous normal tissue. The variant, missing exon 5, inhibits p21 and Bax production and increases cell number. After prolactin stimulation, only full-length Stat5a in
PMID 24384092

Ex-vivo tolerogenic F4/80(+) antigen-presenting cells (APC) induce efferent CD8(+) regulatory T cell-dependent suppression of experimental autoimmune uveitis.

Hsu SM1, Mathew R, Taylor AW, Stein-Streilein J.Author information 1Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, National Cheng-Kung University Hospital, Tainan City, Taiwan.AbstractIt is known that inoculation of antigen into the anterior chamber (a.c.) of a mouse eye induces a.c.-associated immune deviation (ACAID), which is mediated in part by antigen-specific local and peripheral tolerance to the inciting antigen. ACAID can also be induced in vivo by intravenous (i.v.) inoculation of ex-vivo-generated tolerogenic antigen-presenting cells (TolAPC). The purpose of this study was to test if in-vitro-generated retinal antigen-pulsed TolAPC suppressed established experimental autoimmune uveitis (EAU). Retinal antigen-pulsed TolAPC were injected i.v. into mice 7 days post-induction of EAU. We observed that retinal antigen-pulsed TolAPC suppressed the incidence and severity of the clinical expression of EAU and reduced the expression of associated inflammatory cytokines. Moreover, extract of whole retina efficiently replaced interphotoreceptor retinoid-binding protein (IRBP) in the preparation of TolAPC used to induce tolerance in EAU mice. Finally, the suppression of EAU could be transferred to a new set of EAU mice with CD8(+) but not with CD4(+) regulatory T cells (Treg ). Retinal antigen-pulsed TolAPC suppressed ongoing EAU by inducing CD8(+) Treg cells that, in turn, suppressed the effector activity of the IRBP-specific T cells and altered the clinical symptoms of autoimmune inflammation in the eye. The ability to use retinal extract for the antigen raises the possibility that retinal extract could be used to produce autologous TolAPC and then used as therapy in human uveitis.
Clinical and experimental immunology.Clin Exp Immunol.2014 Apr;176(1):37-48. doi: 10.1111/cei.12243.
It is known that inoculation of antigen into the anterior chamber (a.c.) of a mouse eye induces a.c.-associated immune deviation (ACAID), which is mediated in part by antigen-specific local and peripheral tolerance to the inciting antigen. ACAID can also be induced in vivo by intravenous (i.v.) inoc
PMID 24266626

Japanese Journal

ビタミンA核内受容体機能制御剤の開発と医薬応用に関する研究

ビタミン = Vitamins 91(2), 121-128, 2017-02
NAID 40021110211

白血病治療薬剤ATRAの新規標的分子,プロリン異性化酵素Pin1 (特集代謝と血液疾患)

血液内科 = Hematology 73(4), 491-496, 2016-10
NAID 40020984307

An Open-labeled, Multicenter Phase II Study of Tamibarotene in Patients with Steroid-refractory Chronic Graft-versus-Host Disease

Acta Medica Okayama 70(5), 409-412, 2016-10
NAID 120005859873

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