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Tamibarotene

Description of Tamibarotene: Tamibarotene is an orally active, synthetic retinoid, developed to overcome all-trans retinoic acid (ATRA) resistance, with potential antineoplastic activity. As a specific retinoic acid receptor (RAR) alpha/beta agonist, tamibarotene is approximately ten times more potent than ATRA in inducing cell differentiation and apoptosis in HL-60 (human promyelocytic leukemia) cell lines in vitro. Due to a lower affinity for cellular retinoic acid binding protein (CRABP), tamibarotene may show sustained plasma levels compared to ATRA. In addition, this agent may exhibit a lower toxicity profile than ATRA, in part, due to the lack of affinity for the RAR-gamma receptor, the major retinoic acid receptor in the dermal epithelium. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Current developer:   Innovive Pharmaceuticals Inc; CytRx Corporation.

Tamibarotene is currently being developed by CytRx Corporation. According to CytRx Corporation's webpages, Tamibarotene was developed to specifically overcome resistance to ATRA. In vitro, tamibarotene is approximately 10 times more potent than ATRA at causing APL cells to differentiate and die. In addition, tamibarotene has a lower affinity for cellular retinoic acid binding protein, or CRABP, which we believe should allow for sustained plasma levels during administration. Tamibarotene does not bind the RAR-α receptor, the major retinoic acid receptor in the dermal epithelium. In clinical studies, the rate of RAS appeared to be low.

Tamibarotene is currently approved in Japan for treatment of recurrent APL. There is a Special Protocol Assessment (SPA) in place with the FDA for a Phase 2 clinical trial, known as STAR-1, which is evaluating the efficacy and safety of tamibarotene as a third-line treatment for APL. The STAR-1 trial is ongoing and currently includes six clinical sites in the U.S. CytRx recently reported that, of the 11 patients enrolled in the STAR-1 trial to date, three (27%) achieved a hematologic complete response, and four (36%) a morphologic leukemia-free state. Based on the preliminary results in the clinical trial for third-line APL, CytRx has announced its intention to work with key opinion leaders to design a clinical trial to evaluate tamibarotene in combination with other agents as a first-line treatment for this cancer. CytRx holds the North American and European rights to tamibarotene as a treatment for APL.  The FDA has granted Orphan Drug Designation for APL and Fast Track Designation for the use of tamibarotene in patients with relapsed or refractory APL following treatment with all-trans retinoic acid (ATRA) and arsenic trioxide. In addition, tamibarotene has been granted orphan medicinal product status by the European Medicines Agency for the treatment of APL. The efficacy of orally-administered tamibarotene was demonstrated in two Phase 2 studies conducted in Japan in a total of 63 Japanese subjects with APL. The overall complete response rate in these subjects was 60%. In subjects experiencing their first relapse, the overall complete response rate was 81%.

 1: Kitaoka K, Sano A, Chikahisa S, Yoshizaki K, Séi H. Disturbance of rapid eye movement sleep in senescence-accelerated mouse prone/8 mice is improved by retinoic acid receptor agonist Am80 (Tamibarotene). Neuroscience. 2010 May 19;167(3):573-82. Epub 2010 Feb 4. PubMed PMID: 20138974.

2: Sugitani M, Abe R, Ikarashi N, Ito K, Muratake H, Shudo K, Sugiyama K. Disposition of a new tamibarotene prodrug in mice. Biol Pharm Bull. 2009 Dec;32(12):1997-2001. PubMed PMID: 19952418.

3: Tacke R, Müller V, Büttner MW, Lippert WP, Bertermann R, Daiss JO, Khanwalkar H, Furst A, Gaudon C, Gronemeyer H. Synthesis and pharmacological characterization of Disila-AM80 (Disila-tamibarotene) and Disila-AM580, silicon analogues of the RARalpha-selective retinoid agonists AM80 (Tamibarotene) and AM580. ChemMedChem. 2009 Nov;4(11):1797-802. PubMed PMID: 19790202.

4: Kawahara K, Nishi K, Suenobu M, Ohtsuka H, Maeda A, Nagatomo K, Kuniyasu A, Staufenbiel M, Nakagomi M, Shudo K, Nakayama H. Oral administration of synthetic retinoid Am80 (Tamibarotene) decreases brain beta-amyloid peptides in APP23 mice. Biol Pharm Bull. 2009 Jul;32(7):1307-9. PubMed PMID: 19571405.

5: Fukui T, Kodera Y, Nishio K, Masuda N, Tamura T, Koizumi F. Synergistic interactions between the synthetic retinoid tamibarotene and glucocorticoids in human myeloma cells. Cancer Sci. 2009 Jun;100(6):1137-43. PubMed PMID: 19514122.

6: Nakazato T, Okudaira T, Ishikawa C, Nakama S, Sawada S, Tomita M, Uchihara JN, Taira N, Masuda M, Tanaka Y, Ohshiro K, Takasu N, Mori N. Anti-adult T-cell leukemia effects of a novel synthetic retinoid, Am80 (Tamibarotene). Cancer Sci. 2008 Nov;99(11):2286-94. Epub 2008 Sep 1. PubMed PMID: 18771528.

7: Miwako I, Kagechika H. Tamibarotene. Drugs Today (Barc). 2007 Aug;43(8):563-8. Review. PubMed PMID: 17925887.

8: Sanda T, Kuwano T, Nakao S, Iida S, Ishida T, Komatsu H, Shudo K, Kuwano M, Ono M, Ueda R. Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis. Leukemia. 2005 Jun;19(6):901-9. PubMed PMID: 15843826.

9: Tamibarotene: AM 80, retinobenzoic acid, Tamibaro. Drugs R D. 2004;5(6):359-62. Review. PubMed PMID: 15563242.

10: Shudo K, Kagechika H, Yamazaki N, Igarashi M, Tateda C. A synthetic retinoid Am80 (tamibarotene) rescues the memory deficit caused by scopolamine in a passive avoidance paradigm. Biol Pharm Bull. 2004 Nov;27(11):1887-9. Erratum in: Biol Pharm Bull. 2005 Dec;28(12):2346. PubMed PMID: 15516744.

11: Zhang XH, Zheng B, Han M, Miao SB, Wen JK. Synthetic retinoid Am80 inhibits interaction of KLF5 with RAR alpha through inducing KLF5 dephosphorylation mediated by the PI3K/Akt signaling in vascular smooth muscle cells. FEBS Lett. 2009 Apr 17;583(8):1231-6. Epub 2009 Mar 16. PubMed PMID: 19292987.

12: Klemann C, Raveney BJ, Klemann AK, Ozawa T, von Hörsten S, Shudo K, Oki S, Yamamura T. Synthetic retinoid AM80 inhibits Th17 cells and ameliorates experimental autoimmune encephalomyelitis. Am J Pathol. 2009 Jun;174(6):2234-45. Epub 2009 Apr 23. PubMed PMID: 19389933; PubMed Central PMCID: PMC2684188.

13: Takenaga M, Ohta Y, Tokura Y, Hamaguchi A, Shudo K, Okano H, Igarashi R. The effect of Am-80, a synthetic retinoid, on spinal cord injury-induced motor dysfunction in rats. Biol Pharm Bull. 2009 Feb;32(2):225-31. PubMed PMID: 19182380.

14: Miwako I, Shudo K. Oral administration of synthetic retinoid Am80 inhibits the development of type 1 diabetes in non-obese diabetic (NOD) mice. Biol Pharm Bull. 2009 Jan;32(1):157-9. PubMed PMID: 19122301.

15: Satoh T, Higuchi Y, Kawakami S, Hashida M, Kagechika H, Shudo K, Yokoyama M. Encapsulation of the synthetic retinoids Am80 and LE540 into polymeric micelles and the retinoids' release control. J Control Release. 2009 Jun 19;136(3):187-95. Epub 2009 Mar 14. PubMed PMID: 19289148.

16: Jimi S, Mashima K, Matsumoto T, Hara S, Suzumiya J, Tamura K. RARalpha is a regulatory factor for Am-80-induced cell growth inhibition of hematologic malignant cells. Int J Oncol. 2007 Aug;31(2):397-404. PubMed PMID: 17611697.

17: Komaroff AL. By the way, doctor. I am 80 and am taking a 40-milligram Crestor pill every day. Recently I saw a Crestor ad that said blood tests should be done to monitor for possible side effects of liver or muscle injury. Can you tell me something about those tests? Harv Health Lett. 2007 Mar;32(5):8. PubMed PMID: 17390496.

18: Takeda N, Manabe I, Shindo T, Iwata H, Iimuro S, Kagechika H, Shudo K, Nagai R. Synthetic retinoid Am80 reduces scavenger receptor expression and atherosclerosis in mice by inhibiting IL-6. Arterioscler Thromb Vasc Biol. 2006 May;26(5):1177-83. Epub 2006 Feb 16. PubMed PMID: 16484594.

19: Fujiu K, Manabe I, Ishihara A, Oishi Y, Iwata H, Nishimura G, Shindo T, Maemura K, Kagechika H, Shudo K, Nagai R. Synthetic retinoid Am80 suppresses smooth muscle phenotypic modulation and in-stent neointima formation by inhibiting KLF5. Circ Res. 2005 Nov 25;97(11):1132-41. Epub 2005 Oct 13. PubMed PMID: 16224062.

20: Wang T, Nagai H, Bouda K, Matsuura S, Takaoka Y, Niwa S, Homma T, Tanaka H, Shudo K. Effect of selective IL-6 inhibitor Am-80 on experimental autoimmune encephalomyelitis in DA rats. Acta Pharmacol Sin. 2000 Nov;21(11):967-76. PubMed PMID: 11501064.

21: Itoh M, Kominami G. On-line immunoaffinity extraction followed by high-performance liquid chromatography and radioimmunoassay for a novel retinobenzoic acid, AM-80, in human plasma. J Immunoassay Immunochem. 2001;22(3):213-23. PubMed PMID: 11506273.

22: Shinjo K, Takeshita A, Ohnishi K, Sakura T, Miyawaki S, Hiraoka A, Takeuchi M, Tomoyasu S, Wakita H, Ata K, Fukutani H, Ueda R, Ohno R; Koseisho Leukemia Study Group. Good prognosis of patients with acute promyelocytic leukemia who achieved second complete remission (CR) with a new retinoid, Am80, after relapse from CR induced by all-trans-retinoic acid. Int J Hematol. 2000 Dec;72(4):470-3. PubMed PMID: 11197214.

23: Wang T, Niwa S, Bouda K, Matsuura S, Homma T, Shudo K, Nagai H. The effect of Am-80, one of retinoids derivatives on experimental allergic encephalomyelitis in rats. Life Sci. 2000 Sep 1;67(15):1869-79. PubMed PMID: 11043609.

24: Niwa S, Ochi T, Hirano Y, Wang T, Inagaki N, Shudo K, Nagai H. Effect of Am-80, a retinoid derivative, on 2, 4-dinitrofluorobenzene-induced contact dermatitis in mice. Pharmacology. 2000 May;60(4):208-14. PubMed PMID: 10828746.

25: Nagai H, Matsuura S, Bouda K, Takaoka Y, Wang T, Niwa S, Shudo K. Effect of Am-80, a synthetic derivative of retinoid, on experimental arthritis in mice. Pharmacology. 1999 Feb;58(2):101-12. PubMed PMID: 9873234.

26: Tobita T, Takeshita A, Kitamura K, Ohnishi K, Yanagi M, Hiraoka A, Karasuno T, Takeuchi M, Miyawaki S, Ueda R, Naoe T, Ohno R. Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. Blood. 1997 Aug 1;90(3):967-73. PubMed PMID: 9242525.

27: Takeuchi M, Yano T, Omoto E, Takahashi K, Kibata M, Shudo K, Ueda R, Ohno R, Harada M. Re-induction of complete remission with a new synthetic retinoid, Am-80, for relapse of acute promyelocytic leukaemia previously treated with all-trans retinoic acid. Br J Haematol. 1997 Apr;97(1):137-40. PubMed PMID: 9136955.

28: Takeshita A, Shibata Y, Shinjo K, Yanagi M, Tobita T, Ohnishi K, Miyawaki S, Shudo K, Ohno R. Successful treatment of relapse of acute promyelocytic leukemia with a new synthetic retinoid, Am80. Ann Intern Med. 1996 May 15;124(10):893-6. PubMed PMID: 8610919.

29: Hashimoto S, Mizobuchi M, Kuroda T, Okabe H, Mizojiri K, Takahashi S, Kikuchi J, Terui Y. Biotransformation of a new synthetic retinoid, 4-[(5,6,7, 8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl] benzoic acid (Am-80), in the rat. Structure elucidation of the metabolites by mass and nmr spectrometry. Xenobiotica. 1994 Dec;24(12):1177-93. PubMed PMID: 7771105.

30: Von Schroeder HP, Hashimoto Y, Heersche JN. The effects of natural and synthetic retinoids on the differentiation of RCJ C5.18 chondrogenic cells. Teratology. 1994 Jul;50(1):54-62. PubMed PMID: 7974255.