Dose dependent inhibition of uridine phosphorylase (UP) by eniluracil (EU): Was the clinical inferiority of the EU/5-fluorouracil (5-FU) phase III trials due to an unrecognized inhibition of 5-FU anabolism?

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2058-2058 ◽  
Author(s):  
J. Fourie ◽  
V. Guarcello ◽  
R. B. Diasio
Keyword(s):  
Phosphate Buffer ◽  
Competitive Inhibition ◽  
Dihydropyrimidine Dehydrogenase ◽  
Phase Iii ◽  
Uridine Phosphorylase ◽  
Dose Ratio ◽  
Hek 293 ◽  
Phase Iii Trials ◽  
Dose Dependent ◽  
The Eu

2058 Background: Eniluracil (EU) is an irreversible inactivator of dihydropyrimidine dehydrogenase (DPD). EU inhibits DPD dependent 5-fluorouracil (5-FU) catabolism, allowing for oral 5-FU administration with essentially complete bioavailability. Although earlier murine studies suggested an increased antitumor effect when EU was administered before 5-FU, clinical studies used co-administered EU and 5-FU (ratio: 10 EU:1 5-FU) (b.i.d.). These phase III trials demonstrated inferiority compared to a regimen of 5-FU/leukovorin, leading to discontinuation of EU development. We hypothesize that the clinical failure of this EU/5-FU schedule may have resulted from competitive inhibition of 5-FU anabolic (ANA) activation by EU. In this study we examined whether EU could competitively inhibit uridine phosphorylase (UP) or orotate phosphoribosyl transferase (OPRT), the primary ANA enzymes of 5-FU. Methods: The cytoplasmic fraction of human embryonic kidney cells (HEK-293) was used as the source of UP and OPRT. Reverse phase HPLC with radioactivity detection was used to quantify [2-14C]-uracil formation from [2-14C]-uridine (UP activity) and to quantify [6-14C]-FUMP formation from [6-14C]-5-FU (OPRT activity). For UP activity, reaction mixtures consisted of increasing concentrations of EU in phosphate buffer containing 150 μM [2-14C]-uridine. For OPRT activity, reaction mixtures consisted of increasing concentrations of EU in phosphate buffer containing 5 μM [6-14C]-FU and 100 μM benzylacyclouridine (UP inhibitor). Reactions were initiated with addition of UP/OPRT enzyme source and allowed to proceed for 30 min at 37°C. Results: EU displayed dose-dependent competitive inhibition of UP activity (IC50 = 0.375 mM). In particular, the EU/5-FU ratio of 2.5:1 produced approximately 50% inhibition of UP activity. In contrast, EU did not inhibit OPRT activity. Conclusions: This study demonstrates that EU competitively inhibits UP, an important enzyme in 5-FU ANA activation, and suggests that changing the dose ratio and/or increasing the interval between EU and 5-FU administration may be useful in optimizing 5-FU antitumor efficacy. [Table: see text]

Elucidating the mechanisms responsible for the previous failure of phase III clinical trials with eniluracil (EU) and development of a novel scheduling approach to optimize the efficacy of EU/5-fluorouracil (5-FU) combination therapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2557-2557
Author(s):  
V. Guarcello ◽  
J. Fourie ◽  
M. J. Lawton ◽  
W. W. Peters ◽  
M. J. Heslin ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Competitive Inhibition ◽  
Dihydropyrimidine Dehydrogenase ◽  
Phase Iii ◽  
Clinical Failure ◽  
Peripheral Blood Mononuclear ◽  
Phase Iii Clinical Trials ◽  
Phase Iii Trials ◽  
Dosing Regimens

2557 Background: Irreversible inhibition of dihydropyrimidine dehydrogenase (DPD) by EU blocks 5-FU catabolism allowing for oral 5-FU administration with complete bioavailability. Unfortunately, phase III trials with co-administered EU/5-FU showed inferiority vs. 5-FU/leucovorin, and were discontinued. We recently reported that competitive inhibition of human uridine phosphorylase (UP) and thymidine phosphorylase (TP) 5-FU-anabolic enzymes by EU is an important mechanism potentially responsible for clinical failure of the combined EU/5- FU regimen. We hypothesize that EU inhibition of UP and TP is transient, while that of DPD is prolonged, allowing for novel schedule dependent optimization of EU/5-FU dosing regimens with improved efficacy. Methods: In this phase I study, five patients received a single oral dose (2 mg, 5 mg or 10 mg) of EU 12–14 hours prior to scheduled resection of primary/metastatic colorectal cancer. Dosage was as follows: Two patients received the 2 mg dose, one patient received the 5 mg dose and two patients received the 10 mg dose. Matched normal and tumor tissue biopsies were immediately snap frozen and subsequently UP, TP and DPD activity was measured in vitro via HPLC detection of [6- 14C]-5-FU catabolites/anabolites. Peripheral blood mononuclear cell (PBMC) DPD activity was determined at baseline prior to EU administration, 30 min prior to surgery (Day 1), and on Days 2, 5 and 14 following EU administration. Results: At 12–14 hours following EU administration, there was an absence of inhibition of UP and TP, while DPD was significantly inhibited in matched tumor and normal tissue. Importantly, PBMC DPD activity was significantly inhibited by EU on Day 1 (12–14 hours after EU administration) and Day 2 (36 hours after EU administration) at 0 ± 0% and 17 ± 11% (mean ± SD) of baseline, respectively. Conclusions: These data demonstrate a differential recovery time of EU mediated inhibition of UP and TP compared to DPD, which permits future schedule dependent optimization of EU/5-FU therapy. No significant financial relationships to disclose.

scholarly journals Number of clinical trials of new therapeutic agents in the European Union countries of Central and Eastern Europe, 2000–2019

2021 ◽  
Author(s):  
Mikołaj Bartoszkiewicz ◽  
Joanna Kufel-Grabowska ◽  
Maria Litwiniuk
Keyword(s):  
European Union ◽  
Clinical Trials ◽  
Clinical Research ◽  
Eastern Europe ◽  
Central And Eastern Europe ◽  
Phase Iii ◽  
The European Union ◽  
Eu Countries ◽  
Phase Iii Trials ◽  
The Eu

Introduction: The clinical research market of the European Union (EU) countries of Central and Eastern Europe has been experiencing a dynamic growth of clinical trials in the last 10 years. Oncology and cardiology are the areas where the most clinical trials are conducted. Aim: This study aims to analyze the clinical research market including countries, medical fields and trial phases in the EU countries of Central and Eastern Europe. The comparative analysis of countries is divided into 5-year periods. Material and methods: Clinical research market analysis was carried out in 11 EU countries of Central and Eastern Europe: Bulgaria, Croatia, Czechia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Slovakia, and Slovenia. In searching for the number of clinical trials, the ClinicalTrials.gov database was used. Results and discussion: From 2000 to 2019, 6497 clinical trials were conducted in the EU countries of Central and Eastern Europe. There were 1840 clinical trials registered in Poland, 1188 in Czechia, and 1005 in Hungary. The most clinical trials were registered in the field of oncology (22%), followed by cardiology (16%) and neurology (12%). Phase III trials representing as much as 60% (n = 2854) of all conducted medical experiments. The highest increase in the number of clinical trials in the last two 5-year periods (2010–2014 and 2015–2019) was recorded in Estonia, at 471%. Conclusions: There has been a significant increase in the number of clinical phase III trials in the EU countries of Central and Eastern Europe, mainly in Poland, Czechia, and Hungary.

Inhibition kinetics for propionate degradation using propionate-enriched mixed cultures

1998 ◽  
Vol 38 (8-9) ◽  
pp. 443-451 ◽  
Author(s):  
S. H. Hyun ◽  
J. C. Young ◽  
I. S. Kim
Keyword(s):  
Phase I ◽  
Competitive Inhibition ◽  
Gas Production ◽  
Phase Iii ◽  
Utilization Rate ◽  
Inhibition Kinetics ◽  
Wide Range ◽  
Propionate Degradation ◽  
Acetate Utilization ◽  
Velocity Coefficient

To study propionate inhibition kinetics, seed cultures for the experiment were obtained from a propionate-enriched steady-state anaerobic Master Culture Reactor (MCR) operated under a semi-continuous mode for over six months. The MCR received a loading of 1.0 g propionate COD/l-day and was maintained at a temperature of 35±1°C. Tests using serum bottle reactors consisted of four phases. Phase I tests were conducted for measurement of anaerobic gas production as a screening step for a wide range of propionate concentrations. Phase II was a repeat of phase I but with more frequent sampling and detailed analysis of components in the liquid sample using gas chromatography. In phase III, different concentrations of acetate were added along with 1.0 g propionate COD/l to observe acetate inhibition of propionate degradation. Finally in phase IV, different concentrations of propionate were added along with 100 and 200 mg acetate/l to confirm the effect of mutual inhibition. Biokinetic and inhibition coefficients were obtained using models of Monod, Haldane, and Han and Levenspiel through the use of non-linear curve fitting technique. Results showed that the values of kp, maximum propionate utilization rate, and Ksp, half-velocity coefficient for propionate conversion, were 0.257 mg HPr/mg VSS-hr and 200 mg HPr/l, respectively. The values of kA, maximum acetate utilization rate, and KsA, half-velocity coefficient for acetate conversion, were 0.216 mg HAc/mg VSS-hr and 58 mg HAc/l, respectively. The results of phase III and IV tests indicated there was non-competitive inhibition when the acetate concentration in the reactor exceeded 200 mg/l.

Clinical implications and outcomes of the ORION Phase III trials

2020 ◽  
Author(s):  
Julia Brandts ◽  
Kausik K Ray
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Phase Iii ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density Lipoprotein Cholesterol ◽  
Clinical Safety ◽  
Phase Iii Trials ◽  
Phase Ii And Iii ◽  
Ongoing Phase

Inclisiran is a siRNA inhibiting hepatic PCSK9 synthesis. As a first-in-class therapy, inclisiran has been assessed within the ORION trial program for its low-density lipoprotein cholesterol (LDL-C) lowering efficacy and clinical safety. Phase II and III trials have shown that inclisiran lowers LDL-C by about 50% with an infrequent dosing schedule in patients with established atherosclerotic cardiovascular disease and those at high risk, including patients with heterozygous familial hypercholesterolemia. Ongoing Phase III trials will provide evidence on longer-term safety and effectiveness, and inclisiran’s efficacy in patients with homozygous familial hypercholesterolemia. Furthermore, the ORION-4 trial will assess inclisiran’s impact on cardiovascular outcomes.

scholarly journals Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1715
Author(s):  
Robin Park ◽  
Laercio Lopes ◽  
Anwaar Saeed
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Gastroesophageal Cancer ◽  
Programmed Death ◽  
Phase Iii Trials ◽  
Tumor Mutational Burden ◽  
Large Phase ◽  
Programmed Death 1

Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

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