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Assessment of the Safety of Olmesartan in Combination with Sorafenib in Mice Bearing Ehrlich’s Ascites Carcinoma  [PDF]
Mohammad M. Abd-Alhaseeb, Sawsan A. Zaitone, Soad H. Abou-El-Ela, Yasser M. Moustafa
Journal of Cancer Therapy (JCT) , 2013, DOI: 10.4236/jct.2013.48160

Sorafenib was the first multikinase inhibitor to be approved for use in metastatic renal cell carcinoma. Olmesartan medoxomil used in treatment of hypertension and was reported to inhibit angiogenesis in several models. The present study was designed to assess the safety of a combination of sorafenib plus olmesartan compared to monotherapies in mice bearing Ehrlich’s ascites carcinoma cell line. Mice were divided to seven groups, 1) normal mice, 2) Ehrlich’s ascites carcinoma control, 3 - 5) olmesartan (3, 10, 30 mg/kg/day), respectively, 6) sorafenib (30 mg/kg/day) and 7) the combination group: mice received olmesartan (30 mg/kg/day) plus sorafenib. All drug treatments continued for 21 days. At the end of the experiment, a complete blood count was performed and kidney and liver functions were estimated. The combination therapy produced a non-significant change in most of the measurements of complete blood count and liver enzymes when compared to normal animals. On the other hand, the combined therapy significantly increased blood urea nitrogen when compared to normal group but did not change the serum creatinine level. Concomitant administration of olmesartan with sorafenib did not significantly augment the toxicity of the later. Therefore; olmesartan might be a safe candidate with sorafenib in treatment of cancer if clinical data proved the benefit of this combination.

The Angiogenic Activity of Ascites in the Course of Ovarian Cancer as a Marker of Disease Progression  [PDF]
Krzysztof Gawrychowski,Grzegorz Szewczyk,Ewa Skopińska-Ró?ewska,Maciej Ma?ecki,Ewa Barcz,Pawe? Kamiński,Magdalena Miedzińska-Maciejewska,Wac?aw ?miertka,Dariusz Szukiewicz,Piotr Skopiński
Disease Markers , 2014, DOI: 10.1155/2014/683757
Abstract: Ovarian cancer cells are able to create invasive implants in the peritoneum and their growth is directly associated with the angiogenetic potential. This effect is probably stimulated by vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), which are both found in ascites. The aim of this study was to assess the influence of ascites produced by ovarian cancer on the angiogenesis. Peritoneal fluid was collected from patients with advanced ovarian cancer; cancer cells were separated from CD45+ leukocytes. Angiogenesis was assessed in mice, after intradermal injection of full cellular suspension together with supernatant or phosphate buffered saline, purified cancer cells suspension, or CD45+ leukocytes suspension. The angiogenesis index (AI) was assessed after 72 hours. VEGF and Il-8 were measured in the supernatant and cellular suspension. AI was the highest in the isolated cancer cells suspensions as well in the group stimulated with supernatant. Both VEGF and IL-8 were high in supernatants from ascites rich in cancer cells (>45%). A significant correlation was revealed between IL-8 concentration and AI. We conclude that ascites in patients with advanced ovarian cancer stimulates angiogenesis and this mechanism is dependent mostly on cancer cells activity and enhanced by cooperation with infiltrating leukocytes. 1. Introduction The ovary is a unique organ as it is characterized by physiological angiogenesis. The development of dominant follicle requires a creation of new vessels, ranging from theca surrounding the follicle. The follicle cells, both thecal and granulose, show proangiogenic activity stimulating the migration and proliferation of endothelial cells [1]. During luteinization, endothelial cells migrate from the theca and form capillaries of the dense vascular network to direct most of the ovarian blood flow toward corpus luteum. The basic proangiogenic factor found in follicle fluid is vascular endothelial growth factor-(VEGF-) stimulated by luteinizing hormone (LH), human chorionic gonadotropin (hCG), and basic fibroblasts growth factor (bFGF), as well as interleukin-8 (IL-8). Their role in an ovary is not only the matter of increased angiogenesis but also the stimulation of proliferation of follicle cells and induction of ovulation by increased permeability of follicle vessels [2]. Pathologic angiogenic activity is the attribute of growing neoplasms, when they reach more than 1-2?mm3 volume. Numerous proangiogenic factors released by solid tumors as well by tumor infiltrating leukocytes have been described so far [3]. There is
Methylnaltrexone Potentiates the Anti-Angiogenic Effects of mTOR Inhibitors
Patrick A Singleton, Nurbek Mambetsariev, Frances E Lennon, Biji Mathew, Jessica H Siegler, Liliana Moreno-Vinasco, Ravi Salgia, Jonathan Moss, Joe GN Garcia
Vascular Cell , 2010, DOI: 10.1186/2040-2384-2-5
Abstract: Methylnaltrexone (MNTX), a peripheral mu opioid receptor (MOR) antagonist, in combination with the mTOR inhibitors temsirolimus and/or rapamycin, was evaluated for inhibition of VEGF-induced human pulmonary microvascular endothelial cell (EC) proliferation and migration as well as in vivo angiogenesis (mouse Matrigel plug assay).MNTX inhibited VEGF-induced EC proliferation and migration with an IC50 of ~100 nM. Adding 10 nM MNTX to EC shifted the IC50 of temsirolimus inhibition of VEGF-induced proliferation and migration from ~10 nM to ~1 nM and from ~50 to ~10 nM respectively. We observed similar effects with rapamycin. On a mechanistic level, we observed that MNTX increased EC plasma membrane-associated tyrosine phosphate activity. Inhibition of tyrosine phosphatase activity (3,4-dephostatin) blocked the synergy between MNTX and temsirolimus and increased VEGF-induced tyrosine phosphorylation of Src with enhanced PI3 kinase and mTOR Complex 2-dependent phosphorylation of Akt and subsequent activation of mTOR Complex 1 (rapamycin and temsirolimus target), while silencing Src, Akt or mTOR complex 2 components blocked VEGF-induced angiogenic events.Our data indicate that MNTX exerts a synergistic effect with rapamycin and temsirolimus on inhibition of VEGF-induced human EC proliferation and migration and in vivo angiogenesis. Therefore, addition of MNTX could potentially lower the dose of mTOR inhibitors which could improve therapeutic index.Recent therapeutic interventions for the inhibition of cancer progression include drugs that target both tumor growth and angiogenesis. Mammalian target of rapamycin (mTOR) inhibitors, including sirolimus (rapamycin) and temsirolimus, are potential therapeutic agents for hepatocellular cancer and renal cell carcinoma due to their anti-proliferative and anti-angiogenic properties. However, these mTOR inhibitors are often associated with unwanted side effects including rash, asthenia, mucositis, nausea, edema, anemia, hyperglycemia
Synthesis, Characterization and Anti-Angiogenic Effects of Novel 5-Amino Pyrazole Derivatives on Ehrlich Ascites Tumor [EAT] Cells in-Vivo  [PDF]
H. Raju, S. Chandrappa, M. K. Ramakrishna, T. S. Nagamani, H. Ananda, S. M. Byregowda, K. S. Rangappa
Journal of Cancer Therapy (JCT) , 2010, DOI: 10.4236/jct.2010.11001
In search of synthetic chemotherapeutic substances capable of inhibiting, retarding, or reversing the process of multi-stage carcinogenesis, we synthesized a series of novel 5-amino pyrazole derivatives 11(a-h) by a nucleophilic substitution reaction and characterized by 1H nuclear magnetic resonance (NMR), liquid chromatography mass spectrometry (LC/MS), Fourier-transform infrared (FTIR), and elemental analysis. These novel compounds were evaluated for their efficacy in inhibiting Ehrlich ascites tumor [EAT] cells in-vivo. In the present study we designed, synthesized, characterized and investigate the anti-angiogenic effects of these compounds, on Ehrlich ascites tumor [EAT] cells in-vivo. The compounds were subsequently tested for their ability to inhibit neovascularisation in chorio allantoin membrane (CAM) model. From the Structure Activity Relationship (SAR) studies, it reveals that, the substitution at N-terminal in pyrazole ring plays key role in the antitumor and anti-angiogenic effects.
Reversible Decrease of Portal Venous Flow in Cirrhotic Patients: A Positive Side Effect of Sorafenib  [PDF]
Romain Coriat,Hervé Gouya,Olivier Mir,Stanislas Ropert,Olivier Vignaux,Stanislas Chaussade,Philippe Sogni,Stanislas Pol,Benoit Blanchet,Paul Legmann,Fran?ois Goldwasser
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016978
Abstract: Portal hypertension, the most important complication with cirrhosis of the liver, is a serious disease. Sorafenib, a tyrosine kinase inhibitor is validated in advanced hepatocellular carcinoma. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of our study was to determine the effect of sorafenib on portal venous flow and portosystemic collateral circulation in patients receiving sorafenib therapy for advanced hepatocellular carcinoma. Porto-collateral circulations were evaluated using a magnetic resonance technique prior sorafenib therapy, and at day 30. All patients under sorafenib therapy had a decrease in portal venous flow of at least 36%. In contrast, no specific change was observed in the azygos vein or the abdominal aorta. No portal venous flow modification was observed in the control group. Sorafenib is the first anti-angiogenic therapy to demonstrate a beneficial and reversible decrease of portal venous flow among cirrhotic patients.
Hypertension: Focus on Olmesartan Medoxomil
Allison M. Bel,Diane Nykamp
Clinical Medicine : Therapeutics , 2009,
Abstract: Hypertension is the leading cause of stroke, heart failure, and ischemic heart disease. One of the key regulators of blood pressure is the renin-angiotensin aldosterone system (RAAS). Olmesartan medoxomil, an angiotensin receptor blocker (ARB), counteracts some of the primary effects of the RAAS by selectively and irreversibly binding to the type 1 angiotensin II receptor (AT1-R). The pharmacokinetic profile of this ARB allows for the convenience of one a day dosing. The pharmacodynamic profile of olmesartan is favorable because it is neither metabolized by, induces, nor inhibits the CYP450 isozyme system. The metabolism of the prodrug to the active form occurs in the gut by the enzyme arylesterase. No further metabolism and a lack of interaction with the CYP450 isozyme system leads to very few drug interactions with olmesartan medoxomil.Numerous studies have been conducted to evaluate the efficacy, safety, and tolerability of olmesartan medoxomil. Studies have been conducted to compare olmesartan medoxomil to other angiotensin receptor blockers. The efficacy of olmesartan medoxomil has been compared to other classes of antihypertensive agents. Results of all trials have proven non-inferiority of olmesartan medoxomil to other antihypertensive agents; some studies have shown superior blood pressure control provided by olmesartan medoxomil when starting dosages are evaluated. Overall, olmesartan medoxomil has the potential to facilitate the achievement of blood pressure goals, enhance compliance with a once daily dosing regimen, and is associated with minimal side effects. Olmesartan medoxomil has been proven to be a safe and effective antihypertensive drug when compared to other ARBs and other antihypertensive agents.
Cerebrovascular Accidents Associated with Sorafenib in Hepatocellular Carcinoma  [PDF]
Muhammad W. Saif,Iris Isufi,Jennifer Peccerillo,Kostas N. Syrigos
Gastroenterology Research and Practice , 2011, DOI: 10.1155/2011/616080
Abstract: Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. Laboratory data were noncontributory. The head CT scan did not reveal acute abnormalities. No hemodynamically significant stenosis was visible in the carotid ultrasound, and the echocardiogram showed normal size of the heart chambers and normal systolic function of the left ventricle. Sorafenib was discontinued in both cases. Physicians should monitor patients receiving sorafenib for neurologic symptoms, and in the absence of other etiology, prompt discontinuation of this drug should be considered. 1. Background Sorafenib (trade name Nexavar, Bayer Pharmaceuticals, Wayne, NJ, USA) is an orally active multikinase inhibitor that has been approved in the treatment of advanced hepatocellular (HCC) and renal cell carcinoma [1]. Its antineoplastic effect is based on two main mechanisms: the inhibition of both cell proliferation (by inhibiting Raf kinase) and angiogenesis (by inhibiting VEGFR2, VEGFR3, and PDGFR- receptors) [2]. The approval of sorafenib in 2007 for the treatment of HCC was based on the SHARP (Sorafenib in Hepatocarcinoma Carcinoma Assessment Randomized Protocol) study, a multicenter, phase III, double-blind, placebo-controlled trial [3]. The most common adverse reactions observed in patients receiving sorafenib included constitutional symptoms, such as asthenia and fatigue, dermatologic disorders such as hand-foot skin reaction, rash and alopecia, as well as gastrointestinal and liver dysfunction. Hypertension of all grades was reported in 5% and 2% of patients in the sorafenib and placebo group, respectively, ( ). The difference in the incidence of grade 3 hypertension was not statistically significant (2% versus <1%, ) and no grade 4 hypertension reported. The incidences of cardiac ischemia or infarction were similar (3% and 1%) [3]. When data from multiple clinical trials on sorafenib were collected, hypertension crisis, cerebral hemorrhage, myocardial infarction, and chronic heart failure were relatively uncommon (<1%) [4]. However, the documented association between angiogenic inhibitors, such as bevacizumab [5] and sorafenib [6], and thromboembolic
Cirrhotic ascites
Sebati Ozdemir
Medical Journal of Bakirk?y , 2012,
Abstract: Ascites is the accumulation of free uid within the peritoneal cavity. In a patient with new-onset ascites, diagnostic paracentesis should be always performed regardless of the cause. Approximately 85% of cases of ascites are due to liver cirrhosis. In about 15% of patients with ascites, there is nonhepatic cause of uid retention. Ascites is the most common major complication of cirrhosis. Approximately 50% of patients with compensated cirrhosis develop ascites during 10 years of observation, and cirrhotic patients with ascites are associated with a 50% mortality over two years. In this article, clinic, pathophysiologic and diagnostic features and treatment of cirrhotic ascites are reviewed.
Sorafenib Acts through VEGFR-2 Inhibition in a Metastatic Clear-Cell Sarcoma of the Kidney  [PDF]
Tu V. Dao, Thuan V. Tran, Christophe Leb?uf, Morad El-Bouchtaoui, Jér?me Verine, Anne Janin, Guilhem Bousquet
Journal of Cancer Therapy (JCT) , 2016, DOI: 10.4236/jct.2016.77051
Abstract: We report here the case of a young patient with metastatic clear-cell sarcoma of the kidney resistant to standard chemotherapy, and with complete response under sorafenib treatment. The remarkable response of her tumor to sorafenib led us to study sorafenib molecular targets in the metastatic tissue. Background: Biomarkers predicting response to anti-angiogenic tyrosine kinase inhibitors remain to be identified. Methods and Findings: In this paper, we studied the molecular targets of sorafenib in the lung metastasis of a kidney clear-cell sarcoma. In a patient with complete response under sorafenib treatment, we showed high VEGFR2 expression by tumor endothelial cells from the lung metastasis. Conclusion: The original mechanistic results that we obtained using immunostainings and quantitative RT-PCR on laser-microdissected tumor endothelial cells have a direct application in daily clinical practice: metastatic tumors with a large angiogenic component should be tested for VEGFRs expression to consider anti-angiogenic tyrosine kinase inhibitor treatments.
The Professional Medical Journal , 2004,
Abstract: Objectives: To assess the value of adenosine deaminase activity for the diagnosis oftuberculous ascites without performing peritoneal biopsy. Design: Prospective study. Setting: MedicalUnit IV Nishtar Hospital, Multan. Material and Methods: Fifty patients and fifty controls wereincluded in the study. The selection criteria for the patients were history, clinical examination andlymphocytic exudative ascites; and these were labeled as Group-A. While transudative ascites subjectswere kept as control and denoted as Group-B. ADA activity in the ascitic fluid of all the subjects ofGroup-A and Group-B was estimated by Giusti G method. The ADA activity of 40 u/L. Results werestatistically analyzed by applying chi square test. The results would be labeled statistically significant ifp value calculated was <0.05 Results: The ADA activity of the Group-A was 42.4±10.62 u/L while thatof Group-B was 20±10 u/L. Thirty-five in Group-A and five of Group-B had ADA activity above cutoff value (P <0.001). Conclusion: The results favour the application of ADA activity in ascitic fluid asthe diagnostic tool for tuberculosis ascites without performing an invasive procedure like peritonealbiopsy. The study revealed high levels of ADA activity in ascitic fluids of tuberculous patients ascompared to control group (having transudative ascites), 42.4±10.62 u/L and 20.0±10.0u/L respectively.
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