Abstract
The endothelins (ETs), which include ET-1, ET-2, ET-3, and their receptors ET-A and ET-B, play a major role in tumor growth, proliferation, apoptosis, angiogenesis, and bone metastasis. Atrasentan is a novel and selective inhibitor of ET-1 and ET-A. In vitro and in vivo data show that this oral agent is capable of inhibiting tumor cells in vitro. More recently, this agent was studied in several phase I trials with refractory carcinoma patients. Subsequently, phase II and III clinical trials evaluating atrasentan in patients with hormone-refractory prostate carcinoma have suggested that targeting this pathway may be a new therapeutic strategy in the treatment of solid malignancies, specifically, prostate cancer.
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References and Recommended Reading
Levin ER: Endothelins. N Engl J Med 1995, 333:356–363. Hallmark article that describes the major characteristics and function of the endothelins.
Masaki T: The endothelin family: an overview. J Cardiovasc Pharmacol 2000, 35:S3-S5.
Goldie RG: Endothelins in health and disease: an overview. Clin Exp Pharmacol Physiol 1999, 26:145–148.
Bagnato A, Catt KJ: Endothelin as autocrine regulators of tumor cell growth. Trends Endocr Metab 1998, 9:378–383.
Nelson JB, Carducci MA: The role of the endothelin-1 and endothelin receptor antagonists in prostate cancer axis. BJU Int 2000, 85(Suppl2):45–48.
Inoue A, Yanagisawa M, Kimura Y, et al.: The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A 1989, 86:2863–2867.
Nelson J, Bagnato A, Battistini B, Nisen P: The endothelin axis: emerging role in cancer. Nat Rev Cancer 2003, 3:110–116. Article that points out the role of endothelins in cancer.
Battistini B, Chailler P, D’Orleans-Juste P, et al.: Growth regulatory properties of endothelins. Peptides 1993, 14:385–399.
Pristivishalil G, Nelson JB: Endothelium-derived factors as paracrine mediators of prostate cancer progression. Prostate 2000, 44:44–77.
Shichiri M, Kato H, Marumo F, Hirata Y: Endothelin-1 as an autocrine/paracrine apoptosis survival factor for endothelial cells. Hypertension 1997, 30:1198–1203.
Eberl LP, Egidy G, Pinet F, Juillerat-Jeanneret L: Endothelin receptor blockade potentiates FasL-induced apoptosis in colon carcinoma cells via the protein kinase C pathway. J Cardiovasc Pharmacol 2000, 36:S354-S356.
Eberl LP, Valdenaire O, Saintgiorgio V, et al.: Endothelin receptor blockade potentiates FasL-induced apoptosis in rat colon carcinoma cells. Int J 2000, Cancer 2000, 86:182–187.
Nelson JB, Hguyen SH, Wu-Wong JR, et al.: New bone formation in an osteoblastic tumor model is increased by endothelin-1 overexpression and decreased by endothelin A receptor blockade. Urology 1999, 53:1063–1069.
Boyce BF, Yoneda T, Guise TA: Factors regulating the growth of metastatic cancer in bone. Endocr Relat Cancer 1999, 6:333–347.
Mundy GR: Endothelin-1 and osteoblastic metastasis. Proc Natl Acad Sci U S A 2003, 100:10954–10969.
Salani D, Di Castro V, Nicotra MR, et al.: Role of endothelin-1 in neovascularization of ovarian carcinoma. Am J Pathol 2000, 157:1537–1547.
Bek EL, McMillen MA: Endothelins are angiogenic. J Cardiovasc Pharmacol 2000, 36:S135-S139.
Bagnato A, Salani D, Di Castro V, et al.: Expression of endothelin 1 and endothelin A receptor in ovarian carcinoma: evidence for an autocrine role in tumor growth. Cancer Res 1999, 59:720–727.
Salani D, Taraboletti G, Rosano L, et al.: Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Am J Pathol 2000, 157:1703–1711.
Spinella F, Rosano L, Di Castro V, et al.: Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor 1alpha in ovarian cancer cells. J Biol Chem 2002, 277:27850–27855.
Rosano L, Varmi M, Salani D, et al.: Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells. Cancer Res 2001, 61:8340–8346.
Rosano L, Salani D, Di Castro V, et al.: Endothelin-1 promotes proteolytic activity of ovarian carcinoma. Clin Sci 2002, 103:306S-309S.
Thevarajah S, Udan MS, Zheng H, et al.: Endothelin axis expression in renal cell carcinoma. J Urol 1999, 161:137.
Bagnato A, Tecce R, Moretti C, et al.: Autocrine actions of endothelin-1 as a growth factor in human ovarian carcinoma cells. Clin Cancer Res 1995, 1:1059–1066.
Moraitis S, Langdon SP, Miller WR: Endothelin expression and responsiveness in human ovarian carcinoma cell lines. Eur J Cancer 1997, 33:661–668.
Gohji K, Kitazawa S, Tamada H, et al.: Expression of endothelin receptor A associated with prostate cancer progression. J Urol 2001, 165:1033–1036.
Yamashita J, Ogawa M, Inada K, et al.: A large amount of endothelin-1 is present in human breast cancer tissues. Res Commun Chem Pathol Pharmacol 1991, 74:363–369.
Alanen K, Deng DX, Chakrabarti S: Augmented expression of endothelin-1, endothelin-3 and the endothelin-B receptor in breast carcinoma. Histopathology 2000, 36:161–167.
Asham E, Shankar A, Loizidou M, et al.: Increased endothelin-1 in colorectal cancer and reduction of tumour growth by ETA receptor antagonism. Br J Cancer 2001, 85:1759–1763.
Egidy G, Juillerat-Jeanneret L, Jeannin JF, et al.: Modulation of human colon tumor-stromal interactions by the endothelin system. Am J Pathol 2000, 157:1863–1874.
Zhao YD, Xu LX, Chandler JW, et al.: Localization and characterization of endothelin-1 receptor binding in the blood vessels of human pulmonary tumors. J Cardiovasc Res 1995, 26:S341-S345.
Ahmed SI, Thompson J, Coulson JM, Woll PJ: Studies on the expression of endothelin, its receptor subtypes, and converting enzymes in lung cancer and in human bronchial epithelium. Am J Respir Cell Mol Biol 2000, 22:422–431.
Yohn JJ, Smith C, Stevens T, et al.: Human melanoma cells express functional endothelin-1 receptors. Biochem Biophys Res Commun 1994, 201:449–457.
Kikuchi K, Nakagawa H, Kadono T, et al.: Decreased ET(B) receptor expression in human metastatic melanoma cells. Biochem Biophys Res Commun 1996, 219:734–739.
Eberle J, Weitmann S, Thieck O, et al.: Downregulation of endothelin B receptor in human melanoma cell lines parallel to differentiation genes. J Invest Dermatol 1999, 112:925–932.
Demunter A, De Wolf-Peeters C, Degreef H, et al.: Expression of the endothelin-B receptor in pigment cell lesions of the skin: evidence for its role as tumor progression marker in malignant melanoma. Virchows Arch 2001, 438:485–491.
Nambi P, Wu HL, Lipshutz D, Prabhakar U: Identification and characterization of endothelin receptors on rat osteoblastic osteosarcoma cells: down-regulation by 1,25-dihydroxy-vitamin D3. Mol Pharmacol 1995, 47:266–271.
Grimshaw MJ, Naylor S, Balkwill FR: Endothelin-2 is a hypoxia-induced autocrine survival factor for breast tumor cells. Mol Cancer Ther 2002, 14:1273–1281.
Salani D, Rosano L, Di Castro V, et al.: ABT-627, a potent endothelin receptor A antagonist, inhibits ovarian carcinoma growth in-vitro. Clin Sci 2002, 103:318S-321S.
Venuti A, Salani D, Manni V, et al.: Expression of endothelin 1 and endothelin A receptor in HPV-associated cervical carcinoma: new potential targets for anticancer therapy. FASEB J 2000, 14:2277–2283.
Bagnato A, Cirilli A, Salani D, et al.: Growth inhibition of cervix carcinoma cells in vivo by endothelin A receptor blockade. Cancer Res 2002, 62:6381–6384.
Papandreou CN, Usmani B, Geng Y, et al.: Neutral endopeptidase 24.11 loss in metastatic human prostate cancer contributes to androgen independent progression. Nat Med 1998, 4:50–57.
Walden PD, Ittmann M, Monaco ME, Lepor H: Endothelin-1 production and agonist activities in cultured prostate-derived cells: implications for regulation of endothelin bioactivity and bioavailability in prostatic hyperplasia. Prostate 1998, 34:241–250.
Nelson JB, Lee WH, Nguyen SH, et al.: Methylation of the 5′ CpG island of the endothelin B receptor gene is common in human prostate cancer. Cancer Res 1997, 57:35–37.
Carducci MA, Nelson JB, Bowling MK, et al.: Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics. J Clin Oncol 2002, 20:2171–2180. One of the most important clinical articles describing the results of phase I to phase III clinical trials using atrasentan, an ET-1/AT selective antagonist.
Ryan CW, Vogelzang NJ, Vokes EE, et al.: Dose-ranging study of the safety and pharmacokinetics of atrasentan in patients with refractory malignancies. Clin Cancer Res 2004, 10:4406–4411. One of the most important clinical articles describing the results of phase I to phase III clinical trials using atrasentan, an ET-1/AT selective antagonist.
Zonnenberg B, Groenewegen G, Janus TJ, et al.: Phase I dose-escalation study of the safety and pharmacokinetics of atrasetan: an endothelin receptor antagonist for refractory prostate cancer. Clin Can Res 2003, 9:2965–2972. One of the most important clinical articles describing the results of phase I to phase III clinical trials using atrasentan, an ET-1/AT selective antagonist.
Carducci M, Padley R, Breul J, et al.: Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol 2003, 21:679–689. One of the most important clinical articles describing the results of phase I to phase III clinical trials using atrasentan, an ET-1/AT selective antagonist.
Carducci M, Nelson JB, Saad F, et al.: Effects of atrasentan on disease progression and biological markers in men with metastatic hormone refractory prostate cancer: phase II study. J Clin Oncol 2004, 22:384S. One of the most important clinical articles describing the results of phase I to phase III clinical trials using atrasentan, an ET-1/AT selective antagonist.
Vogelzang N, Nelson JB, Schulman DP, et al.: Meta-analysis of clinical trials of atrasentan 10mg in metastatic hormone-refractory prostate cancer [abstract]. Proc ASCO 2005, 24:4563. One of the most important clinical articles describing the results of phase I to phase III clinical trials using atrasentan, an ET-1/AT selective antagonist.
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Thakkar, S.G., Choueiri, T.K. & Garcia, J.A. Endothelin receptor antagonists: Rationale, clinical development, and role in prostate cancer therapeutics. Curr Oncol Rep 8, 108–113 (2006). https://doi.org/10.1007/s11912-006-0045-1
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DOI: https://doi.org/10.1007/s11912-006-0045-1