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Atrasentan

Description of atrasentan hydrochloride: atrasentan hydrochloride is the orally available hydrochloride salt of pyrrolidine-3-carboxylic acid with potential antineoplastic activity. As a selective antagonist of the endothelin-A (ETA) receptor, atrasentan binds selectively to the ETA receptor, which may result in inhibition of endothelin-induced angiogenesis and tumor cell proliferation. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:     Abbott Laboratories

Atrasentan hydrochloride  is the orally available hydrochloride salt of pyrrolidine-3-carboxylic acid with potential antineoplastic activity. As a selective antagonist of the endothelin-A (ETA) receptor, atrasentan binds selectively to the ETA receptor, which may result in inhibition of endothelin-induced angiogenesis and tumor cell proliferation.

Atrasentan is an experimental drug that is being studied for the treatment of various types of cancer, including non-small cell lung cancer. It is an endothelin receptor antagonist selective for subtype A (ETA). While other drugs of this type (sitaxentan, ambrisentan) exploit the vasoconstrictive properties of endothelin and are mainly used for the treatment of pulmonary arterial hypertension, atrasentan blocks endothelin induced cell proliferation.

According to http://www.hrpca.org/atrasentan.htm, [Cancer. 2007 Nov 1;110(9):1959-66.] A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Carducci MA, Saad F, brahamsson PA, Dearnaley DP, Schulman CC, North SA, Sleep DJ, Isaacson JD, Nelson JB; for the Atrasentan Phase III Study Group Institutions. Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, Louisiana, June 5-8, 2004. The conclusion states that Atrasentan did not delay disease progression in men with metastatic HRPC despite evidence of biologic effects on PSA and BAP as markers of disease burden.

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17: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Apr;31(3):183-226. PubMed PMID: 19536362.

18: Herrmann E, Tiemann A, Eltze E, Bolenz C, Bremer C, Persigehl T, Hertle L, Wülfing C. Endothelin-A-receptor antagonism with atrasentan exhibits limited activity on the KU-19-19 bladder cancer cell line in a mouse model. J Cancer Res Clin Oncol. 2009 Oct;135(10):1455-62. Epub 2009 May 9. PubMed PMID: 19430814.

19: Motta EM, Chichorro JG, D'Orléans-Juste P, Rae GA. Roles of endothelin ETA and ETB receptors in nociception and chemical, thermal and mechanical hyperalgesia induced by endothelin-1 in the rat hindpaw. Peptides. 2009 May;30(5):918-25. Epub 2009 Feb 7. PubMed PMID: 19428770.

20: Jullien N, Blirando K, Milliat F, Sabourin JC, Benderitter M, François A. Up-regulation of endothelin type a receptor in human and rat radiation proctitis: preclinical therapeutic approach with endothelin receptor blockade. Int J Radiat Oncol Biol Phys. 2009 Jun 1;74(2):528-38. PubMed PMID: 19427554.

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22: Tykocki NR, Gariepy CE, Watts SW. Endothelin ET(B) receptors in arteries and veins: multiple actions in the vein. J Pharmacol Exp Ther. 2009 Jun;329(3):875-81. Epub 2009 Mar 18. PubMed PMID: 19297422; PubMed Central PMCID: PMC2683769.

23: Banfor PN, Franklin PA, Segreti JA, Widomski DL, Davidsen SK, Albert DH, Cox BF, Fryer RM, Gintant GA. ETA receptor blockade with atrasentan prevents hypertension with the multitargeted tyrosine kinase inhibitor ABT-869 in telemetry-instrumented rats. J Cardiovasc Pharmacol. 2009 Feb;53(2):173-8. PubMed PMID: 19188829.

24: Chichorro JG, Zampronio AR, Cabrini DA, Franco CR, Rae GA. Mechanisms operated by endothelin ETA and ETB receptors in the trigeminal ganglion contribute to orofacial thermal hyperalgesia induced by infraorbital nerve constriction in rats. Neuropeptides. 2009 Apr;43(2):133-42. Epub 2009 Jan 20. PubMed PMID: 19157542.

25: Vernerová Z, Kujal P, Kramer HJ, Bäcker A, Cervenka L, Vanecková I. End-organ damage in hypertensive transgenic Ren-2 rats: influence of early and late endothelin receptor blockade. Physiol Res. 2009;58 Suppl 2:S69-78. Review. PubMed PMID: 20131938.

26: Giachini FR, Zemse SM, Carneiro FS, Lima VV, Carneiro ZN, Callera GE, Ergul A, Webb RC, Tostes RC. Interleukin-10 attenuates vascular responses to endothelin-1 via effects on ERK1/2-dependent pathway. Am J Physiol Heart Circ Physiol. 2009 Feb;296(2):H489-96. Epub 2008 Dec 12. PubMed PMID: 19074677; PubMed Central PMCID: PMC2643883.

27: Tomillero A, Moral MA. Gateways to clinical trials. July-August 2008. Methods Find Exp Clin Pharmacol. 2008 Jul-Aug;30(6):459-95. PubMed PMID: 18850047.

28: Armstrong AJ, Creel P, Turnbull J, Moore C, Jaffe TA, Haley S, Petros W, Yenser S, Gockerman JP, Sleep D, Hurwitz H, George DJ. A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer. Clin Cancer Res. 2008 Oct 1;14(19):6270-6. PubMed PMID: 18829508.

29: Carneiro FS, Nunes KP, Giachini FR, Lima VV, Carneiro ZN, Nogueira EF, Leite R, Ergul A, Rainey WE, Clinton Webb R, Tostes RC. Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension. J Sex Med. 2008 Dec;5(12):2793-807. Epub 2008 Sep 24. PubMed PMID: 18823320.

30: Nelson JB, Love W, Chin JL, Saad F, Schulman CC, Sleep DJ, Qian J, Steinberg J, Carducci M; Atrasentan Phase 3 Study Group. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. 2008 Nov 1;113(9):2478-87. PubMed PMID: 18785254.

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32: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 May;30(4):313-31. PubMed PMID: 18773127.

33: Raichlin E, Prasad A, Mathew V, Kent B, Holmes DR Jr, Pumper GM, Nelson RE, Lerman LO, Lerman A. Efficacy and safety of atrasentan in patients with cardiovascular risk and early atherosclerosis. Hypertension. 2008 Sep;52(3):522-8. Epub 2008 Aug 11. PubMed PMID: 18695150; PubMed Central PMCID: PMC2675066.

34: Cella D, Nichol MB, Eton D, Nelson JB, Mulani P. Estimating clinically meaningful changes for the Functional Assessment of Cancer Therapy--Prostate: results from a clinical trial of patients with metastatic hormone-refractory prostate cancer. Value Health. 2009 Jan;12(1):124-9. Epub 2008 Jul 18. PubMed PMID: 18647260.

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37: Honoré JC, Carrier E, Fecteau MH, Tirapelli CR, Bkaily G, D'Orleans-Juste P. Nonselective ETA/ETB-receptor blockade increases systemic blood pressure of Bio 14.6 cardiomyopathic hamsters. Can J Physiol Pharmacol. 2008 Jun;86(6):394-401. PubMed PMID: 18516103.

38: Höhne C, Francis RC, Pickerodt P, Klein A, Kaisers U, Boemke W. ETA-receptor blockade impairs vasoconstriction after hemorrhage in xenon-anesthetized dogs treated with an AT1-receptor antagonist. Can J Physiol Pharmacol. 2008 Jun;86(6):373-9. PubMed PMID: 18516101.

39: Carneiro FS, Giachini FR, Lima VV, Carneiro ZN, Nunes KP, Ergul A, Leite R, Tostes RC, Webb RC. DOCA-salt treatment enhances responses to endothelin-1 in murine corpus cavernosum. Can J Physiol Pharmacol. 2008 Jun;86(6):320-8. PubMed PMID: 18516094; PubMed Central PMCID: PMC2683475.

40: Thakali K, Galligan JJ, Fink GD, Gariepy CE, Watts SW. Pharmacological endothelin receptor interaction does not occur in veins from ET(B) receptor deficient rats. Vascul Pharmacol. 2008 Jul;49(1):6-13. Epub 2008 Apr 3. PubMed PMID: 18485831; PubMed Central PMCID: PMC2529478.

41: Phuphanich S, Carson KA, Grossman SA, Lesser G, Olson J, Mikkelsen T, Desideri S, Fisher JD; New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. Phase I safety study of escalating doses of atrasentan in adults with recurrent malignant glioma. Neuro Oncol. 2008 Aug;10(4):617-23. Epub 2008 May 13. PubMed PMID: 18477765; PubMed Central PMCID: PMC2666236.

42: Sachidanandam K, Elgebaly MM, Harris AK, Hutchinson JR, Mezzetti EM, Portik-Dobos V, Ergul A. Effect of chronic and selective endothelin receptor antagonism on microvascular function in type 2 diabetes. Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2743-9. Epub 2008 Apr 18. PubMed PMID: 18424628.

43: Vernerová Z, Kramer HJ, Bäcker A, Cervenka L, Opocenský M, Husková Z, Vanourková Z, Eis V, Chábová VC, Tesar V, Malý J, Vanecková I. Late-onset endothelin receptor blockade in hypertensive heterozygous REN-2 transgenic rats. Vascul Pharmacol. 2008 Apr-Jun;48(4-6):165-73. Epub 2008 Feb 12. PubMed PMID: 18372220.

44: Chiappori AA, Haura E, Rodriguez FA, Boulware D, Kapoor R, Neuger AM, Lush R, Padilla B, Burton M, Williams C, Simon G, Antonia S, Sullivan DM, Bepler G. Phase I/II study of atrasentan, an endothelin A receptor antagonist, in combination with paclitaxel and carboplatin as first-line therapy in advanced non-small cell lung cancer. Clin Cancer Res. 2008 Mar 1;14(5):1464-9. PubMed PMID: 18316570.

45: Tu SM, Lin SH. Current trials using bone-targeting agents in prostate cancer. Cancer J. 2008 Jan-Feb;14(1):35-9. Review. Erratum in: Cancer J. 2008 May-Jun;14(3):199. PubMed PMID: 18303481.

46: Harris AK, Elgebaly MM, Li W, Sachidanandam K, Ergul A. Effect of chronic endothelin receptor antagonism on cerebrovascular function in type 2 diabetes. Am J Physiol Regul Integr Comp Physiol. 2008 Apr;294(4):R1213-9. Epub 2008 Feb 20. PubMed PMID: 18287215.

47: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Dec;29(10):697-735. PubMed PMID: 18200333.

48: Shahani R, Fleshner NE, Zlotta AR. Pharmacotherapy for prostate cancer: the role of hormonal treatment. Discov Med. 2007 Aug;7(39):118-24. PubMed PMID: 18093474.

49: Lalich M, McNeel DG, Wilding G, Liu G. Endothelin receptor antagonists in cancer therapy. Cancer Invest. 2007 Dec;25(8):785-94. Review. PubMed PMID: 18058475.

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52: Carducci MA, Saad F, Abrahamsson PA, Dearnaley DP, Schulman CC, North SA, Sleep DJ, Isaacson JD, Nelson JB; Atrasentan Phase III Study Group Institutions. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007 Nov 1;110(9):1959-66. PubMed PMID: 17886253.

53: Gorenflo M, Ullmann MV, Herpel E, Neumayer S, Dieckmann R, Demirakca S, Klimpel H, Hagl S, Gebhard MM. Atrasentan treatment of pulmonary vascular disease in piglets with increased pulmonary blood flow. J Cardiovasc Pharmacol. 2007 Sep;50(3):286-92. PubMed PMID: 17878757.

54: Gordi T. Comments on "Dual effects of rifampin on the pharmacokinetics of atrasentan". J Clin Pharmacol. 2007 Sep;47(9):1181; author reply 1182. PubMed PMID: 17766702.

55: Sachidanandam K, Portik-Dobos V, Harris AK, Hutchinson JR, Muller E, Johnson MH, Ergul A. Evidence for vasculoprotective effects of ETB receptors in resistance artery remodeling in diabetes. Diabetes. 2007 Nov;56(11):2753-8. Epub 2007 Aug 1. PubMed PMID: 17670915.

56: Fink G, Li M, Lau Y, Osborn J, Watts S. Chronic activation of endothelin B receptors: new model of experimental hypertension. Hypertension. 2007 Sep;50(3):512-8. Epub 2007 Jul 30. PubMed PMID: 17664390.

57: Elgebaly MM, Portik-Dobos V, Sachidanandam K, Rychly D, Malcom D, Johnson MH, Ergul A. Differential effects of ET(A) and ET(B) receptor antagonism on oxidative stress in type 2 diabetes. Vascul Pharmacol. 2007 Aug-Sep;47(2-3):125-30. Epub 2007 Jun 6. PubMed PMID: 17597010.

58: Wölkart G, Pang X, Stessel H, Kirchengast M, Brunner F. Chronic endothelin-A receptor antagonism is as protective as angiotensin converting enzyme inhibition against cardiac dysfunction in diabetic rats. Br J Pharmacol. 2007 Aug;151(8):1187-97. Epub 2007 Jun 18. PubMed PMID: 17572700; PubMed Central PMCID: PMC2189828.

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62: Smollich M, Götte M, Kersting C, Fischgräbe J, Kiesel L, Wülfing P. Selective ETAR antagonist atrasentan inhibits hypoxia-induced breast cancer cell invasion. Breast Cancer Res Treat. 2008 Mar;108(2):175-82. Epub 2007 Apr 28. PubMed PMID: 17468950.

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66: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jan-Feb;29(1):53-71. PubMed PMID: 17344945.

67: Brand TC, Tolcher AW. Management of high risk metastatic prostate cancer: the case for novel therapies. J Urol. 2006 Dec;176(6 Pt 2):S76-80; discussion S81-2. Review. PubMed PMID: 17084174.

68: Carducci MA, Jimeno A. Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. Clin Cancer Res. 2006 Oct 15;12(20 Pt 2):6296s-6300s. Review. PubMed PMID: 17062717.

69: Opocenský M, Kramer HJ, Bäcker A, Vernerová Z, Eis V, Cervenka L, Certíková Chábová V, Tesar V, Vanecková I. Late-onset endothelin-A receptor blockade reduces podocyte injury in homozygous Ren-2 rats despite severe hypertension. Hypertension. 2006 Nov;48(5):965-71. Epub 2006 Oct 2. PubMed PMID: 17015777.

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71: Tan WW. Novel agents and targets in managing patients with metastatic prostate cancer. Cancer Control. 2006 Jul;13(3):194-8. Review. PubMed PMID: 16885915.

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74: Michaelson MD, Kaufman DS, Kantoff P, Oh WK, Smith MR. Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer. Cancer. 2006 Aug 1;107(3):530-5. PubMed PMID: 16804927.

75: Jimeno A, Carducci M. Atrasentan: a rationally designed targeted therapy for cancer. Drugs Today (Barc). 2006 May;42(5):299-312. Review. PubMed PMID: 16801993.

76: Rumohr JA, Chang SS. Current chemotherapeutic approaches for androgen-independent prostate cancer. Curr Opin Investig Drugs. 2006 Jun;7(6):529-33. Review. PubMed PMID: 16784023.

77: Trentin PG, Fernandes MB, D'Orléans-Juste P, Rae GA. Endothelin-1 causes pruritus in mice. Exp Biol Med (Maywood). 2006 Jun;231(6):1146-51. PubMed PMID: 16741066.

78: Chichorro JG, Zampronio AR, Rae GA. Endothelin ET(B) receptor antagonist reduces mechanical allodynia in rats with trigeminal neuropathic pain. Exp Biol Med (Maywood). 2006 Jun;231(6):1136-40. PubMed PMID: 16741064.

79: Francis RC, Höhne C, Klein A, Donaubauer B, Kaisers U, Boemke W. Endothelin-a receptor blockade does not debilitate the cardiovascular and hormonal adaptation to xenon or isoflurane anesthesia in dogs. Exp Biol Med (Maywood). 2006 Jun;231(6):834-9. PubMed PMID: 16741008.

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81: Wölkart G, Stessel H, Saad Z, Kirchengast M, Brunner F. Cardioprotective effects of atrasentan, an endothelin-A receptor antagonist, but not of nitric oxide in diabetic mice with myocyte-specific overexpression of endothelial nitric oxide synthase. Br J Pharmacol. 2006 Jul;148(5):671-81. Epub 2006 May 15. PubMed PMID: 16702986; PubMed Central PMCID: PMC1751871.

82: Chichorro JG, Zampronio AR, Souza GE, Rae GA. Orofacial cold hyperalgesia due to infraorbital nerve constriction injury in rats: reversal by endothelin receptor antagonists but not non-steroidal anti-inflammatory drugs. Pain. 2006 Jul;123(1-2):64-74. Epub 2006 Mar 24. PubMed PMID: 16563629.

83: Murphy G. Atrasentan for metastatic hormone refractory prostate cancer. Issues Emerg Health Technol. 2005 Dec;(77):1-4. PubMed PMID: 16544441.

84: Katz DA, Carr R, Grimm DR, Xiong H, Holley-Shanks R, Mueller T, Leake B, Wang Q, Han L, Wang PG, Edeki T, Sahelijo L, Doan T, Allen A, Spear BB, Kim RB. Organic anion transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics. Clin Pharmacol Ther. 2006 Mar;79(3):186-96. Epub 2006 Feb 17. PubMed PMID: 16513443.

85: Thakkar SG, Choueiri TK, Garcia JA. Endothelin receptor antagonists: rationale, clinical development, and role in prostate cancer therapeutics. Curr Oncol Rep. 2006 Mar;8(2):108-13. PubMed PMID: 16507220.

86: Mathews WB, Zober TG, Ravert HT, Scheffel U, Hilton J, Sleep D, Dannals RF, Szabo Z. Synthesis and in vivo evaluation of a PET radioligand for imaging the endothelin-A receptor. Nucl Med Biol. 2006 Jan;33(1):15-9. PubMed PMID: 16459254.

87: Cella D, Petrylak DP, Fishman M, Teigland C, Young J, Mulani P. Role of quality of life in men with metastatic hormone-refractory prostate cancer: how does atrasentan influence quality of life? Eur Urol. 2006 May;49(5):781-9. Epub 2006 Jan 19. Review. PubMed PMID: 16458417.

88: Fryer RM, Rakestraw PA, Banfor PN, Cox BF, Opgenorth TJ, Reinhart GA. Blood pressure regulation by ETA and ETB receptors in conscious, telemetry-instrumented mice and role of ETA in hypertension produced by selective ETB blockade. Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2554-9. Epub 2006 Jan 6. PubMed PMID: 16399858.

89: Herrmann E, Bögemann M, Bierer S, Eltze E, Hertle L, Wülfing C. The endothelin axis in urologic tumors: mechanisms of tumor biology and therapeutic implications. Expert Rev Anticancer Ther. 2006 Jan;6(1):73-81. Review. PubMed PMID: 16375646.

90: Berry W, Eisenberger M. Achieving treatment goals for hormone-refractory prostate cancer with chemotherapy. Oncologist. 2005;10 Suppl 3:30-9. Review. PubMed PMID: 16368869.

91: Berthiaume N, Carlson CJ, Rondinone CM, Zinker BA. Endothelin antagonism improves hepatic insulin sensitivity associated with insulin signaling in Zucker fatty rats. Metabolism. 2005 Nov;54(11):1515-23. PubMed PMID: 16253642.

92: Carlson DM, Steinberg JL, Gordon G. Targeting the unmet medical need: the Abbott Laboratories oncology approach. Clin Adv Hematol Oncol. 2005 Sep;3(9):703-10. PubMed PMID: 16224444.

93: Vanêcková I, Kramer HJ, Bäcker A, Vernerová Z, Opocensky M, Cervenka L. Early endothelin-A receptor blockade decreases blood pressure and ameliorates end-organ damage in homozygous Ren-2 rats. Hypertension. 2005 Oct;46(4):969-74. Epub 2005 Sep 12. PubMed PMID: 16157796.

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