endothelin-1 and Pancreatic-Neoplasms

EndoTAG-1 (ET), a novel formulation of cationic liposomes carrying embedded paclitaxel (Taxol), shows antitumoral activity, targeting tumor endothelial cells in solid tumors. Patients with advanced metastatic cancer were evaluated investigating effects on pharmacokinetics and tumor vasculature using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and contrast-enhanced ultrasound (CEUS).. The pharmacokinetic (PK) profile of ET (22 mg/m(2) i.v.) was evaluated after single and repeated doses. DCE-MRI and CEUS explored hepatic metastases before, during and after the 4-week treatment cycle. Angiogenic biomarkers were assessed. Tumor response was evaluated by modified RECIST.. The PK profile demonstrated slight accumulation of paclitaxel after repeated doses. DCE-MRI parameters K(trans) and/or iAUC(60) showed a trend to decrease. Changes of blood flow-dependent parameters of DCE-MRI and CEUS were well correlated. Angiogenic biomarkers revealed no clear trend. ET was generally well tolerated; common toxic effects were fatigue and hypersensitivity reactions. Nine (9 of 18) patients had stable disease after the first treatment cycle. Four patients without disease progression continued treatment.. This study including multiple pretreated patients with different metastatic cancer revealed individually distinctive hemodynamic alterations by DCE-MRI. The PK profiles of ET were similar as observed previously.

Topics: Adult; Aged; Angiogenesis Inhibitors; Angiotensin II; Area Under Curve; Breast Neoplasms; Colorectal Neoplasms; Contrast Media; Endothelin-1; Female; Humans; Interleukins; Liposomes; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Paclitaxel; Pancreatic Neoplasms; Ultrasonography; Vascular Endothelial Growth Factor A

Topics: Amylases; Animals; Ceruletide; Disease Models, Animal; Endothelin-1; Endothelin-Converting Enzymes; Gene Expression Regulation; Humans; Inflammation; Mice; Oncogenes; Pancreatic Neoplasms; Pancreatitis; Proto-Oncogene Proteins p21(ras); Receptor, Endothelin A; Receptor, Endothelin B

Endothelin-1 (ET-1) acting through endothelin A and B receptors (ETAR and ETBR) has been implicated in the development of cancer. The endothelin axis has not previously been characterised in human pancreatic adenocarcinoma (PAC).. Expression of ET-1, ETAR, ETBR, vascular endothelial growth factor and microvessel density (MVD) was determined by immunohistochemistry in 45 surgically resected human PACs and 15 non-cancer human pancreas samples.. PAC had the highest staining intensity for ET-1 and ETBR: 38% PAC samples scored 2+ or more compared with 7% non-cancer sample in ET-1; 58% PAC samples scored 2+ compared with 0% non-cancer samples in ETBR. MVD was significantly lower in PAC compared with non-cancer tissue (p<0.0001).. PAC was characterised by greater expression of ET-1 and ETBR compared with normal pancreas.

Topics: Adenocarcinoma; Biomarkers, Tumor; Case-Control Studies; Endothelin-1; Humans; Immunohistochemistry; Pancreatic Neoplasms; Receptor, Endothelin B; Receptors, Endothelin; Tissue Array Analysis; Up-Regulation

Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors -inexpensive drugs with decades of safe use - could be rapidly repurposed as cancer therapeutics.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensins; Animals; Antineoplastic Agents; Cell Hypoxia; Collagen; Connective Tissue Growth Factor; Drug Repositioning; Drug Synergism; Endothelin-1; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Hyaluronic Acid; Losartan; Mammary Neoplasms, Experimental; Mechanotransduction, Cellular; Mice; Pancreatic Neoplasms; Receptor, Angiotensin, Type 1; Stress, Mechanical; Stromal Cells; Transforming Growth Factor beta1

Pancreatic stellate cells (PSC) play a key role in pancreatic fibrosis. Activation of PSC occurs in response to pro-fibrogenic stimuli and is maintained by autocrine loops of mediators, such as endothelin (ET)-1. Here, we have evaluated effects of the dual ET receptor antagonist bosentan in models of pancreatic fibrogenesis and cancer. Cell culture studies revealed that PSC and DSL6A pancreatic cancer cells expressed both ET-1 and ET receptors. Bosentan efficiently inhibited proliferation of both cell types and collagen synthesis in PSC. Expression of the myofibroblastic marker alpha-smooth muscle actin, connective tissue growth factor, and ET-1 itself in PSC was reduced, while expression of matrix metalloproteinase-9 was enhanced. Like PSC, DSL6A cells secrete less ET-1 when cultured with bosentan. In a rat model of pancreatic fibrosis, chronic pancreatitis induced by dibutyltin dichloride, a tendency towards a diminished disease progression was observed in a subgroup of rats with less severe disease. Together, our results indicate that bosentan exerts antifibrotic and antitumor effects in vitro. Its efficiency in vivo warrants further investigation.

Topics: Animals; Bosentan; Carcinoma; Cell Line, Tumor; Coculture Techniques; Collagen; Endothelin Receptor Antagonists; Endothelin-1; Fibrosis; Organotin Compounds; Pancreas; Pancreatic Neoplasms; Pancreatitis, Chronic; Rats; Receptors, Endothelin; Sulfonamides