Endothelin-secreting tumors and the idea of the pseudoectopic hormone secretion in tumors

Kurbel, Sven; Kurbel, Beatrica; Kovačić, Damir; Šulava, Darko; Krajina, Zdenko; Dmitrović, Branko; Šokčević, Marina

doi:10.1054/mehy.1997.0637

Cited by 25 publications

(12 citation statements)

References 31 publications

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“…Although a small effect of BQ123 alone was observed in the absence of irradiation (probably attributable to the antiproliferative effect of this drug; Refs. [27][28][29], the combination of both irradiation and the ET A antagonist led to a synergistic effect in both irradiation protocols, increasing the tumor regrowth delay by Ͼ50% over the additive effects (see Table 1). We additionally documented that the radiosensitizing effects of BQ123 were very likely to arise from the increase in tumor oxygenation directly associated with the elevation in tumor blood flow (see Fig.…”

Section: Endothelin Antagonism and Tumor Vascularizationmentioning

confidence: 97%

“…In the current study, our reflection started from the growing evidence that endothelin-1 production is increased in many tumor types where it plays crucial roles in proliferation and angiogenesis (27)(28)(29). In these studies, however, there was no mention of the powerful vasoconstrictive effects of endothelin-1 (ET-1) and its potential action on the contractile tone of tumor vessels.…”

Section: Introductionmentioning

confidence: 99%

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Endothelin-1 Is a Critical Mediator of Myogenic Tone in Tumor Arterioles

Sonveaux¹,

Dessy²,

Martinive³

et al. 2004

Cancer Research

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Although derived from the host tissue, the tumor vasculature is under the influence of the tumor microenvironment and needs to adapt to the resistance to blood flow inherent to the dynamics of tumor growth. Such vascular remodeling can offer selective targets to pharmacologically modulate tumor perfusion and thereby improve the efficacy of conventional anticancer treatments. Radiotherapy and chemotherapy can, indeed, take advantage of a better tumor oxygenation and drug delivery, respectively, both partly dependent on the tumor blood supply.Here, we showed that isolated tumor arterioles mounted in a pressure myograph have the ability, contrary to size-matched healthy arterioles, to contract in response to a transluminal pressure increase. This myogenic tone was exquisitely dependent on the endothelin-1 pathway because it was completely abolished by the selective endothelin receptor A (ET A ) antagonist BQ123. This selectivity was additionally supported by the large increase in endothelin-1 abundance in tumors and the higher density of the ET A receptors in tumor vessels. We also documented by using laser Doppler microprobes and imaging that administration of the ET A antagonist led to a significant increase in tumor blood flow, whereas the perfusion in control healthy tissue was not altered. Finally, we provided evidence that acute administration of the ET A antagonist could significantly stimulate tumor oxygenation, as determined by electron paramagnetic resonance oximetry, and increase the efficacy of low-dose, clinically relevant fractionated radiotherapy.Thus, blocking the tumor-selective increase in the vascular endothelin-1/ ET A pathway led us to unravel an important reserve of vasorelaxation that can be exploited to selectively increase tumor response to radiotherapy.

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Section: Endothelin Antagonism and Tumor Vascularizationmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Endothelin-1 Is a Critical Mediator of Myogenic Tone in Tumor Arterioles

Sonveaux¹,

Dessy²,

Martinive³

et al. 2004

Cancer Research

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“…Extensive preclinical and clinical studies, mainly with ETA receptor antagonists, have shown excellent therapeutic benefits in the treatment of cardiovascular disorders (7)(8)(9)(10)(11). Increasing evidence also shows that endothelin promotes tumor growth via its mitogenic and angiogenic effects (12)(13)(14). The design of potent and selective nonpeptide antagonists of endothelin-1 is vital to defining the role of endothelin in human diseases.…”

mentioning

confidence: 99%

Synthesis and In Vivo Evaluation of Novel PET Radioligands for Imaging the Endothelin-A Receptor

Mathews

Murugesan

Xia³

et al. 2008

J Nucl Med

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The endothelin subtype-A (ETA) receptor is a member of a family of G-protein-coupled receptors that plays a central role in vasoconstriction, cell proliferation, and hormone production. The aim of this study was to synthesize and evaluate in vivo 11 C-and 18 F-labeled analogs of the potent and selective ETA antagonist N- [[29-[[(4,5-dimethyl-3-isoxazolyl) ,3,3-trimethylbutanamide (BMS-207940). Methods: Protected precursors and authentic nonradioactive standards were synthesized by reductive amination and subsequent alkylation of protected aldehyde 1. Desmethyl precursor 2 was reacted with 11 C-methyl iodide followed by deprotection and high-performance liquid chromatography purification to produce 11 C-(N-[[29-[[(4,5-Nitro precursor 4 was reacted with 18 F-fluoride and purified by high-performance liquid chromatography to produce 18 F-(N-[[29-[[(4,5-Biodistribution was determined by injecting male CD-1 mice via the tail vein with either 11 C-BMS-5p 3 or 18 F-FBzBMS 5. Specific binding was determined by pretreatment with 1 mg of BMS-207940 per kilogram. PET scanning of a baboon using either 11 C-BMS-5p 3 or 18 F-FBzBMS 5 was performed at baseline and 40 min after intravenous administration of 1 mg of BMS-207940 per kilogram. Results: 11 C-BMS-5p 3 was synthesized with 1.5% radiochemical yield in 36 min, with an average specific activity of 1,051 GBq/mmol (28,400 mCi/mmol; n 5 5) at the end of synthesis. 18 F-FBzBMS 5 was synthesized with 0.54% radiochemical yield in 130 min, with an average specific activity of 12.9 GBq/mmol (349 mCi/mmol, n 5 7) at the end of synthesis. In mice, the highest uptake of both radioligands was in the liver, lungs, and heart. Radioactivity in the liver washed out over time, and uptake in the lungs and heart remained relatively stable. Mice pretreated with 1 mg of BMS-207940 per kilogram showed greater than 64% specific binding in the lungs and kidneys at 60 min. Specific binding in the heart was determined to be 63% for 11 C-BMS-5p 3 and 81% for 18 F-FBzBMS 5. PET studies in a baboon showed high uptake of both radioligands in the myocardium. Between 35 and 85 min, the heart-to-blood ratio was 4.7 to 1. Pretreatment with a 1 mg/kg dose of BMS-207940 showed 85% specific binding in the myocardium at 85 min after injection. Conclusion: Both 11 C-BMS-5p 3 and 18 F-FBzBMS 5 bind selectively to the ETA receptor in vivo. Further development of these radioligands for imaging the ETA receptor in humans is warranted.

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“…Endothelin-1 was first described as a potent endogenous vasoconstrictor peptide, but is now also known to play important roles in tissue differentiation, repair, development, cell proliferation, hormone production, angiogenesis, matrix remodelling and apoptosis. It is primarily produced by endothelial, vascular smooth muscle and epithelial cells and has also been detected in many different tumours (Bagnato et al, 1999;Kurbel et al, 1999;Nelson et al, 2003).…”

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confidence: 99%

The endothelin B (ETB) receptor agonist IRL 1620 is highly vasoconstrictive in two syngeneic rat tumour lines: potential for selective tumour blood flow modification

et al. 2005

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The vascular effects of the endothelin B (ET B ) receptor agonist IRL 1620 were investigated in the rat P22 carcinosarcoma and a range of normal tissues in BDIX rats. Tissue blood flow rate was calculated from measurements of tissue uptake of radiolabelled iodoantipyrine. A comparison of vascular effects in the P22 tumour and the HSN sarcoma growing in CBH/CBi rats was made using laser Doppler flowmetry, showing similar effects of IRL 1620, with red cell flux rapidly decreasing by 50 -60% and then returning to control levels within approximately 30 min. This corresponded to similar levels but different spatial organisation of ET B binding sites in the two tumours, as measured by autoradiography. The decrease in tumour blood flow and an increase in vascular resistance suggest that the vascular component of ET B receptors in the P22 tumour is localised on contractile elements rather than on endothelial cells. ET A receptors were also identified. Vasoconstriction occurred uniformly throughout the P22 tumour mass, consistent with a measured homogeneous distribution of ET B receptors. IRL 1620 caused vasoconstriction in normal skeletal muscle, kidney and small intestine of the BDIX rat as well as in tumour, but did not affect blood flow in other tissues. These effects could be useful for limiting toxicity of certain chemotherapeutic agents. Fully functional ET B receptors are clearly expressed on tumour vasculature and IRL 1620 shows promise for short-term modification of tumour blood flow. Expression levels of ET B receptors on the tumour vasculature could be useful for predicting which tumours are likely to respond to IRL 1620.

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Endothelin-secreting tumors and the idea of the pseudoectopic hormone secretion in tumors

Cited by 25 publications

References 31 publications

Endothelin-1 Is a Critical Mediator of Myogenic Tone in Tumor Arterioles

Endothelin-1 Is a Critical Mediator of Myogenic Tone in Tumor Arterioles

Synthesis and In Vivo Evaluation of Novel PET Radioligands for Imaging the Endothelin-A Receptor

The endothelin B (ETB) receptor agonist IRL 1620 is highly vasoconstrictive in two syngeneic rat tumour lines: potential for selective tumour blood flow modification

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