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BioRxiv : the Preprint Server For... Sep 2023Pulmonary arterial hypertension (PAH) is a progressive and potentially a rapidly fatal disease characterized by vasoconstriction and remodeling of small pulmonary...
Pulmonary arterial hypertension (PAH) is a progressive and potentially a rapidly fatal disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PA) leading to increased pulmonary vascular resistance and right heart failure. Central to the remodeling process is a switch of the smooth muscle cells in small PAs (PASMC) to a proliferative, apoptosis-resistant phenotype. There is reason to suspect that the plasminogen activator system may play an important role in the remodeling program in PAH based on its roles in vascular post-injury restenosis, fibrosis, angiogenesis and tumorigenesis. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of the plasminogen activators - urokinase-type and tissue-type (uPA and tPA, respectively). Immunohisto- chemical and immunoblot analyses revealed that PAI-1 was deficient in smooth muscle areas of small remodeled PAs and early-passage PASMC from subjects with PAH compared to non-PAH controls. male and female mice developed spontaneous pulmonary vascular remodeling and pulmonary hypertension (PH) as evidenced by significant increase in PA medial thickness, systolic right ventricular pressure, and right ventricular hypertrophy. Lastly, the uPA inhibitors upamostat (WX-671) and amiloride analog BB2-30F down-regulated mTORC1 and SMAD3, restored PAI-1 levels, reduced proliferation, and induced apoptosis in human PAH PASMC. We examined the effect of inhibition of uPA catalytic activity by BB2-30F on the development of SU5416/Hypoxia (SuHx)-induced PH in mice. Vehicletreated SuHx-exposed mice had up-regulated mTORC1 in small PAs, developed pulmonary vascular remodeling and PH, as evidenced by significant increase of PA MT, sRVP, RV hypertrophy, and a significant decrease in the pulmonary artery acceleration time/pulmonary ejection time (PAAT/PET) ratio compared to age- and sex-matched normoxia controls, whereas BB2-30F-treated group was protected from all these pathological changes. Taken together, our data strongly suggest that PAI-1 down- regulation in PASMC from human PAH lungs promotes PASMC hyper-proliferation, remodeling, and spontaneous PH due to unopposed uPA activation. Further studies are needed to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate the progression and/or reverse pulmonary vascular remodeling and PH.
PubMed: 37790328
DOI: 10.1101/2023.09.21.558893 -
BMC Cancer May 2015To evaluate the in vivo response by detecting the anti-angiogenic and invasion-inhibiting effects of a triple-combination-therapy in an...
BACKGROUND
To evaluate the in vivo response by detecting the anti-angiogenic and invasion-inhibiting effects of a triple-combination-therapy in an experimental-small-animal-squamous-cell-carcinoma-model using the "flash-replenishment" (FR) method to assess tissue hemodynamics via contrast-enhanced-ultrasound (CEUS).
METHODS
Human hypopharynx-carcinoma-cells were subcutaneously injected into the left flank of 22-female-athymic-nude-rats. After seven days of subcutaneous tumor growth, FR-measurements were performed on each rat. Treatment-group and control-group were treated every day for a period of one week, with the treatment-group receiving solvents containing a triple therapy of Upamostat®, Celecoxib® and Ilomastat® and the control-group solvents only. On day seven, follow-up measurements were performed using the same measurement protocol to assess the effects of the triple therapy. VueBox® was used to quantify the kinetic parameters and additional immunohistochemistry analyses were performed for comparison with and validation of the CEUS results against established methods (Proliferation/Ki-67, vascularization/CD31, apoptosis/caspase3).
RESULTS
Compared to the control-group, the treatment-group that received the triple-therapy resulted in a reduction of tumor growth by 48.6% in size. Likewise, the immunohistochemistry results showed significant decreases in tumor proliferation and vascularization in the treatment-group in comparison to the control-group of 26%(p ≤ 0.05) and 32.2%(p ≤ 0.05) respectively. Correspondingly, between the baseline and follow-up measurements, the therapy-group was associated with a significant(p ≤ 0.01) decrease in the relative-Blood-Volume(rBV) in both the whole tumor(wt) and hypervascular tumor(ht) areas (p ≤ 0.01), while the control-group was associated with a significant (p ≤ 0.01) increase of the rBV in the wt area and a non-significant increase (p ≤ 0.16) in the ht area. The mean-transit-time (mTT) of the wt and the ht areas showed a significant increase (p ≤ 0.01) in the follow-up measurements in the therapy group.
CONCLUSION
The triple-therapy is feasible and effective in reducing both tumor growth and vascularization. In particular, compared with the placebo-group, the triple-therapy-group resulted in a reduction in tumor growth of 48.6% in size when assessed by CEUS and a significant reduction in the number of vessels in the tumor of 32% as assessed by immunohistochemistry. As the immunohistochemistry supports the CEUS findings, CEUS using the "flash replenishment"(FR) method appears to provide a useful assessment of the anti-angiogenic and invasion-inhibiting effects of a triple combination therapy.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Celecoxib; Cell Line, Tumor; Cell Proliferation; Female; Humans; Hydroxamic Acids; Hypopharyngeal Neoplasms; Indoles; Neovascularization, Pathologic; Oximes; Piperazines; Rats; Sulfonamides; Treatment Outcome; Ultrasonography; Xenograft Model Antitumor Assays
PubMed: 25947947
DOI: 10.1186/s12885-015-1333-7 -
International Journal of Infectious... Mar 2023We performed a pilot study of upamostat, a serine protease inhibitor, in outpatients with symptomatic COVID-19 before a pivotal trial. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
We performed a pilot study of upamostat, a serine protease inhibitor, in outpatients with symptomatic COVID-19 before a pivotal trial.
METHODS
SARS-CoV-2 patients with ≥2 moderate-severe symptoms onset within 5 days were randomized to oral upamostat 200 or 400 mg or placebo daily for 14 days. Patients completed COVID-19 symptom questionnaires daily for 28 days, then thrice weekly for 4 weeks, and underwent physical and laboratory examinations periodically.
RESULTS
A total of 61 patients enrolled of which 20 received a placebo or upamostat 200 mg daily; 21 received upamostat 400 mg daily. Treatment was well tolerated; only one patient (upamostat 400) reported a drug-related adverse event, mild skin rash; no patient discontinued owing to a drug-related adverse event. The median time to a sustained recovery from severe symptoms was 8, 4, and 3 days for the three treatment groups, respectively. New severe symptoms developed in 20% of the placebo group vs 2.4% in the combined upamostat groups, (P = 0.036). Three placebo patients (15%) versus no upamostat patients were hospitalized for worsening COVID (P= 0.03). The mean d-dimer level remained constant in placebo patients but decreased by 38% and 48% in upamostat 200 and 400 patients, respectively.
CONCLUSION
Upamostat was well tolerated, shortened recovery time, and decreased new severe symptoms and hospitalization.
Topics: Humans; COVID-19; SARS-CoV-2; Pilot Projects; Outpatients; Serine Proteinase Inhibitors; Treatment Outcome; Double-Blind Method
PubMed: 36549549
DOI: 10.1016/j.ijid.2022.12.003 -
Cancers Mar 2024Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the...
Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts.
Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.
PubMed: 38473407
DOI: 10.3390/cancers16051050 -
British Journal of Cancer Mar 2013To evaluate the efficacy and tolerability of the urokinase plasminogen activator (uPA) inhibitor upamostat in combination with gemcitabine in locally advanced pancreatic... (Randomized Controlled Trial)
Randomized Controlled Trial
Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer.
BACKGROUND
To evaluate the efficacy and tolerability of the urokinase plasminogen activator (uPA) inhibitor upamostat in combination with gemcitabine in locally advanced pancreatic adenocarcinoma (LAPC).
METHODS
Within a prospective multicenter study, LAPC patients were randomly assigned to receive 1000 mg m(-2) of gemcitabine IV weekly either alone (arm A) or in combination with 200 mg (arm B) or 400 mg (arm C) oral upamostat daily. Efficacy endpoints of this proof-of-concept study included response rate, time to first metastasis, progression-free and overall survival (OS).
RESULTS
Of the 95 enroled patients, 85 were evaluable for response and 93 for safety. Median OS was 12.5 months (95% CI 8.2-18.2) in arm C, 9.7 months (95% CI 8.4-17.1) in arm B and 9.9 months (95% CI 7.4-12.1) in arm A; corresponding 1-year survival rates were 50.6%, 40.7% and 33.9%, respectively. More patients achieved a partial remission (confirmed responses by RECIST) with upamostat combination therapy (arm C: 12.9%; arm B: 7.1%; arm A: 3.8%). Overall, only 12 patients progressed by developing detectable distant metastasis (arm A: 4, arm B: 6, arm C: 2). The most common adverse events considered to be related to upamostat were asthenia, fever and nausea.
CONCLUSION
In this proof-of-concept study targeting the uPA system in LAPC, the addition of upamostat to gemcitabine was tolerated well; similar survival results were observed for the three treatment arms.
Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Proteins; Deoxycytidine; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Oximes; Pancreatic Neoplasms; Piperazines; Sulfonamides; Gemcitabine
PubMed: 23412098
DOI: 10.1038/bjc.2013.62 -
British Journal of Cancer Apr 2013CYFRA 21-1 serves as biomarker in several epithelial malignancies. However, its role in pancreatic cancer (PC) has not yet been investigated. (Clinical Trial)
Clinical Trial
BACKGROUND
CYFRA 21-1 serves as biomarker in several epithelial malignancies. However, its role in pancreatic cancer (PC) has not yet been investigated.
METHODS
Within a prospective single-centre study serial blood samples were collected from patients with confirmed advanced PC. Pre-treatment values and weekly measurements of CYFRA 21-1, carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (assessed by Elecsys 2010, Roche Diagnostics) during palliative first-line chemotherapy were obtained. Biomarker data were correlated with objective response (determined by RECIST) as well as time to progression (TTP) and overall survival (OS) using uni- and multivariate analyses.
RESULTS
Seventy-eight patients were included, 45% of these received treatment in prospective clinical trials. Median TTP was 3.9 months, median OS 7.7 months. Pre-treatment CYFRA 21-1 levels were significantly associated with performance status (P=0.0399) and stage of disease (P=0.0001). Marker values before chemotherapy and at the 2-month staging of all three markers were considered significant predictors for objective treatment response. Pre-treatment CYFRA 21-1 levels, as well as CA 19-9 values, could be applied to define subgroups (categorised by tertiles) with a different OS outcome (CYFRA: 14.8 vs 7.1 vs 4.8 months, CA 19-9: 14.2 vs 7.1 vs 5.2 months; P<0.0001). CYFRA 21-1 and CA 19-9 (both as categorised and as continuous variables) showed a highly significant correlation with TTP and OS at nearly all-time points assessed in univariate analysis. In multivariate analysis, only CYFRA 21-1 and performance status were independent predictors for OS.
CONCLUSIONS
CYFRA 21-1 may serve as a valuable tool for monitoring treatment response and assessing prognosis in advanced PC.
Topics: Adult; Aged; Albumins; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Biomarkers, Tumor; CA-19-9 Antigen; Capecitabine; Carcinoembryonic Antigen; Deoxycytidine; Disease-Free Survival; Erlotinib Hydrochloride; Everolimus; Fluorouracil; Humans; Imidazoles; Indazoles; Keratin-19; Middle Aged; Multivariate Analysis; Oximes; Paclitaxel; Palliative Care; Pancreatic Neoplasms; Piperazines; Prospective Studies; Quinazolines; Sirolimus; Sulfonamides; Survival Rate; Gemcitabine
PubMed: 23579210
DOI: 10.1038/bjc.2013.158