Endothelin Receptor Expression in Colorectal Cancer

Ali, H; Dashwood, Michael R.; Dawas, Khaled; Loizidou, M; Savage, F; Taylor, I.

doi:10.1097/00005344-200036051-00023

Cited by 42 publications

(17 citation statements)

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“…Differences in responses by individual fibroblast strains would be further determined by the original amounts of endogenous ET-1 produced by each individual strain. Although not measured in the fibroblast strains studied here, we have previously reported varied endogenous ET-1 production by different cell lines (19). The present findings, considered in the wider context of fibroblast studies, show both strong overall patterns of colonic fibroblast response but also the importance of individual-specific differences.…”

Section: Discussionsupporting

confidence: 58%

“…Receptor binding studies were conducted as described previously (19): cytospins and tissue homogenates were incubated in increasing 125 I-ET-1 concentrations (GE, specific activity 2,200 Ci/mmol: 3 Â 10 À12 -10 À9 mol/L) with nonspecific binding established in the presence of unlabeled ET-1(1 mmol/L). After incubation; slides were postfixed in paraformaldehyde vapor; and homogenates filtered and washed (3Â).…”

Section: Zibotentan Et a Receptor Binding Characteristicsmentioning

confidence: 99%

“…Immunohistochemistry was conducted using the Vectastain Alkaline Phosphatase Kit (Vector Labs) following manufacturer's instructions as described previously (5,19). Primary antibodies used were AS02/Thy-1 for fibroblasts, CD31 for vascular endothelial cells, anti-ET A receptor and anti-ET B receptor antibodies (Alomone Labs), Col11A1 for collagen Type XI (Santa Cruz Biotech, Inc; 1:200 in PBS, 30 minutes), followed by universal secondary antibody (1:100 in normal horse serum/PBS, 10 minutes).…”

Section: Zibotentan Et a Receptor Binding Characteristicsmentioning

confidence: 99%

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Efficacy of the Specific Endothelin A Receptor Antagonist Zibotentan (ZD4054) in Colorectal Cancer: A Preclinical Study

Haque

Dashwood

Heetun

et al. 2013

Molecular Cancer Therapeutics

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Endothelin 1 (ET-1) is overexpressed in cancer, contributing to disease progression. We previously showed that ET-1 stimulated proliferative, migratory, and contractile tumorigenic effects via the ET A receptor. Here, for the first time, we evaluate zibotentan, a specific ET A receptor antagonist, in the setting of colorectal cancer, in cellular models. Pharmacologic characteristics were further determined in patient tissues. Colorectal cancer lines (n ¼ 4) and fibroblast strains (n ¼ 6), isolated from uninvolved areas of colorectal cancer specimens, were exposed to ET-1 and/or ET A/B receptor antagonists. Proliferation (methylene blue), migration (scratch wounds), and contraction (gel lattices) were assessed. Receptor distribution and binding characteristics (K d , B max ) were determined using autoradiography on tissue sections and homogenates and cytospun cells, supported by immunohistochemistry. Proliferation was inhibited by ET A (zibotentan > BQ123; P < 0.

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Section: Discussionsupporting

confidence: 58%

Section: Zibotentan Et a Receptor Binding Characteristicsmentioning

confidence: 99%

Section: Zibotentan Et a Receptor Binding Characteristicsmentioning

confidence: 99%

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Efficacy of the Specific Endothelin A Receptor Antagonist Zibotentan (ZD4054) in Colorectal Cancer: A Preclinical Study

Haque

Dashwood

Heetun

et al. 2013

Molecular Cancer Therapeutics

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“…Increased ET A R expression has been reported in a broad range of human cancers, including prostate, (30) ovarian, (12) breast, (31) colon, (32) lung, (33) cervical, (13) renal (34) and thyroid gland. (35) Overexpression of ET A R is generally associated with a more malignant phenotype.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

Qiang

Zeng²,

Feng³

et al. 2006

Cancer Science

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The endothelin A receptor (ET A R) autocrine pathway is overexpressed in many malignancies, including nasopharyngeal carcinoma (NPC). In this tumor, ET A R expression is an independent determinant of survival and a robust independent predictor of distant metastasis. To evaluate whether ET A R represents a new target in NPC treatment, we tested the therapeutic role of ET A R in NPC. N asopharyngeal carcinoma is common in Southern China, with an annual incidence of 15-50 cases per 100 000 people.(1) NPC is distinct from other epithelial malignancies in the head and neck region in that it affects a relatively young population and has a propensity for distant metastases.(2) NPC is a radiosensitive tumor for which there is a high local control rate after radical radiotherapy. However, for patients with locoregionally advanced disease, the rate of distant metastasis is high and the 5-year overall survival rate is poor.(3) Randomized trials have confirmed that chemotherapy improves the distant metastasis control rate in patients with locoregionally advanced NPC; however, approximately 20% or more of the patients still have distant metastasis develop despite intensive chemotherapy.(4,5) These findings underscore the need to develop novel strategies in the management of patients with advanced NPC.The family of ET, including ET-1, ET-2 and ET-3, are 21-amino acid peptides exerting many biological effects.(6) Two major receptor subtypes belonging to the G protein-coupled family of receptors mediate ET signals: ET A R, which binds ET-1 and ET-2 with high affinity and ET-3 with low affinity; and ET B R, which binds all ET isopeptides with equal affinity.(7) ET-1, which is the most common circulating form of ET, is produced by many epithelial tumors.(8) ET-1 induces cell proliferation directly or synergistically with other growth factors that are relevant in cancer progression. Engagement of ET A R by ET-1 triggers activation of tumor proliferation, (9-13) VEGF-induced angiogenesis, (14,15) invasiveness (16) and inhibition of apoptosis. (17,18) The ET-1-ET A R autocrine pathway has a key role in the development and progression of prostatic, ovarian and cervical cancers.(9) The major relevance of ET A R in tumor development has led to an extensive search of highly selective antagonists. ABT-627 (Atrasentan), one such antagonist, is orally bioavailable and has suitable pharmacokinetic and toxicity profiles for clinical use. (19,20) ABT-627 has been given to cancer patients in phase II trials for prostate cancer and delayed the time to clinical and prostate-specific antigen progression.(21) Two pivotal randomized, double-blind, placebo-controlled, multinational phase III trials are ongoing in patients with hormone-refractory prostate cancer to verify these findings.We reported previously that patients with advanced-stage NPC had elevated plasma big ET-1 levels compared with the levels in healthy control participants; high pretreatment plasma big ET-1 levels are generally associated with post-treatment distant failure.(22) Our pr...

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“…In addition to its mitogenic effects, ET-1 has also been found to contribute to tumour growth by protecting tumour cells from apoptosis (Eberl et al, 2000b). Increased ET A R expression has been demonstrated in malignant tissue in several cancer types including ovarian, prostate and colorectal cancer, whereas in normal tissue from these sites ET B R predominates (Nelson et al, 1996;Bagnato et al, 1999;Ali et al, 2000).…”

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confidence: 99%

Expression of Endothelin-A-Receptor predicts unfavourable response to neoadjuvant chemotherapy in locally advanced breast cancer

et al. 2004

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Endothelin-1 (ET-1) and its receptors (ET A R and ET B R), referred to as the endothelin (ET) axis, are overexpressed in breast carcinomas and appear to influence tumour growth and progression. The objective of this study was to determine the effect of expression of the ET axis in breast carcinomas on response to cytotoxic chemotherapy. The study included 44 patients with locally advanced breast cancer participating in a prospective phase III study evaluating high-dose neoadjuvant chemotherapy of epirubicin and cyclophosphamide. Expression of ET-1, ET A R and ET B R was determined by semiquantitative immunohistochemical analysis of breast cancer tissue from prechemotherapy tru-cut biopsies. Immunohistochemical staining was positive for ET-1 in 61.5%, for ET A R in 35% and for ET B R in 35.9% of breast carcinomas. Pathological response to chemotherapy was significantly decreased in ET A Rpositive patients (P ¼ 0.002). In total, 50% of ET A R-positive patients as compared to 7.7% of ET A R-negative patients attained pathologically 'no change'. Logistic regression confirmed ET A R as an independent predictive marker for pathological response (P ¼ 0.009). These data indicate that increased expression of ET A R in breast carcinomas is associated with resistance to chemotherapy. Determination of ET A R status may serve as a predictive marker for identifying patients less likely to be responsive to conventional chemotherapy.

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Endothelin Receptor Expression in Colorectal Cancer

Cited by 42 publications

References 0 publications

Efficacy of the Specific Endothelin A Receptor Antagonist Zibotentan (ZD4054) in Colorectal Cancer: A Preclinical Study

Efficacy of the Specific Endothelin A Receptor Antagonist Zibotentan (ZD4054) in Colorectal Cancer: A Preclinical Study

Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

Expression of Endothelin-A-Receptor predicts unfavourable response to neoadjuvant chemotherapy in locally advanced breast cancer

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