This open-label, single-arm phase II study examined efficacy, safety, pharmacokinetics, and biomarkers of histone deacetylase (HDAC) inhibitor resminostat in patients with relapsed or refractory Hodgkin lymphoma. Thirty-seven heavily pretreated patients received 600 (19 patients) or 800 mg (18 patients) oral resminostat daily for the initial 5 days of 14-day treatment cycles. Objective response rate (ORR) (primary) was 34% reaching disease control in 54% patients. Most patients (69%) showed reduced tumor size and reduced [18F]-FDG uptake in target lesions (71%). Median progression-free survival (PFS) was 2.3 months (95%CI [1.3; 3.3]) and median overall survival (OS) was 12.5 months (95%CI [9.6; 18.6]). Patients who responded or stabilized under resminostat had a 10-month longer OS than patients who progressed. Efficacy assessment, pharmacodynamics, and exploratory biomarker results followed plasma levels, showed target engagement and epigenetic modulations. Common drug-related adverse events (AEs) were nausea, vomiting, anemia, thrombocytopenia, and fatigue, mainly grade 1 or 2.
- Klíčová slova
- Hodgkin lymphoma, Resminostat, epigenetics, histone deacetylase,
- MeSH
- antitumorózní látky aplikace a dávkování škodlivé účinky farmakokinetika terapeutické užití MeSH
- biologické markery MeSH
- chemorezistence MeSH
- dospělí MeSH
- Hodgkinova nemoc diagnóza farmakoterapie etiologie mortalita MeSH
- inhibitory histondeacetylas aplikace a dávkování škodlivé účinky farmakokinetika terapeutické užití MeSH
- Kaplanův-Meierův odhad MeSH
- kyseliny hydroxamové aplikace a dávkování škodlivé účinky farmakokinetika terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- opakovaná terapie MeSH
- PET/CT MeSH
- pozitronová emisní tomografie MeSH
- recidiva MeSH
- senioři MeSH
- sulfonamidy aplikace a dávkování škodlivé účinky farmakokinetika terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- Názvy látek
- antitumorózní látky MeSH
- biologické markery MeSH
- inhibitory histondeacetylas MeSH
- kyseliny hydroxamové MeSH
- resminostat MeSH Prohlížeč
- sulfonamidy MeSH
4-Carboxy-α-[3-(hydroxyamino)-3-oxopropyl]-benzenepropanoic acid 1 is a potent hydroxamate-based inhibitor of glutamate carboxypeptidase II. In an attempt to improve its poor oral pharmacokinetics, we synthesized a series of prodrugs by masking its hydrophilic hydroxamate group. Prodrugs were evaluated for oral availability in mice and showed varying degree of plasma exposure to 1. Of these, para-acetoxybenzyl-based, 4-(5-(((4-acetoxybenzyl)oxy)amino)-2-carboxy-5-oxopentyl)benzoic acid, 12, provided 5-fold higher plasma levels of 1 compared to oral administration of 1 itself. Subsequently, para-acetoxybenzyl-based prodrugs with additional ester promoiety(ies) on carboxylate(s) were examined for their ability to deliver 1 to plasma. Isopropyloxycarbonyloxymethyl (POC) ester 30 was the only prodrug that achieved substantial plasma levels of 1. In vitro metabolite identification studies confirmed stability of the ethyl ester of benzoate while the POC group was rapidly hydrolyzed. At oral daily dose-equivalent of 3 mg/kg, 12 exhibited analgesic efficacy comparable to dose of 10 mg/kg of 1 in the rat chronic constrictive injury model of neuropathic pain.
- MeSH
- analgetika chemie farmakokinetika farmakologie terapeutické užití MeSH
- aplikace orální MeSH
- esterifikace MeSH
- glutamátkarboxypeptidasa II antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů chemie farmakokinetika farmakologie terapeutické užití MeSH
- krysa rodu Rattus MeSH
- kyseliny hydroxamové chemie farmakokinetika farmakologie terapeutické užití MeSH
- lidé MeSH
- myši MeSH
- neuralgie farmakoterapie enzymologie MeSH
- objevování léků MeSH
- potkani Sprague-Dawley MeSH
- prekurzory léčiv chemie farmakokinetika farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- analgetika MeSH
- glutamátkarboxypeptidasa II MeSH
- inhibitory enzymů MeSH
- kyseliny hydroxamové MeSH
- prekurzory léčiv MeSH
Positron emission tomography (PET) as well as optical imaging (OI) with peptide receptor targeting probes have proven their value for oncological applications but also show restrictions depending on the clinical field of interest. Therefore, the combination of both methods, particularly in a single molecule, could improve versatility in clinical routine. This proof of principle study aims to show that a chelator, Fusarinine C (FSC), can be utilized as scaffold for novel dimeric dual-modality imaging agents. Two targeting vectors (a minigastrin analogue (MG11) targeting cholecystokinin-2 receptor overexpression (CCK2R) or integrin αVβ3 targeting cyclic pentapeptides (RGD)) and a near-infrared fluorophore (Sulfo-Cyanine7) were conjugated to FSC. The probes were efficiently labeled with gallium-68 and in vitro experiments including determination of logD, stability, protein binding, cell binding, internalization, and biodistribution studies as well as in vivo micro-PET/CT and optical imaging in U-87MG αVβ3- and A431-CCK2R expressing tumor xenografted mice were carried out. Novel bioconjugates showed high receptor affinity and highly specific targeting properties at both receptors. Ex vivo biodistribution and micro-PET/CT imaging studies revealed specific tumor uptake accompanied by slow blood clearance and retention in nontargeted tissues (spleen, liver, and kidneys) leading to visualization of tumors at early (30 to 120 min p.i.). Excellent contrast in corresponding optical imaging studies was achieved especially at delayed time points (24 to 72 h p.i.). Our findings show the proof of principle of chelator scaffolding for hybrid imaging agents and demonstrate FSC being a suitable bifunctional chelator for this approach. Improvements to fine-tune pharmacokinetics are needed to translate this into a clinical setting.
- MeSH
- chelátory chemie farmakokinetika MeSH
- heterografty MeSH
- integrin alfaVbeta3 metabolismus MeSH
- kyseliny hydroxamové farmakokinetika MeSH
- lidé MeSH
- molekulární sondy chemie farmakokinetika MeSH
- multimodální zobrazování metody MeSH
- myši MeSH
- nádorové buňky kultivované MeSH
- nádory diagnostické zobrazování metabolismus MeSH
- PET/CT MeSH
- radioizotopy galia farmakokinetika MeSH
- receptor cholecystokininu B metabolismus MeSH
- železité sloučeniny farmakokinetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- chelátory MeSH
- fusigen MeSH Prohlížeč
- integrin alfaVbeta3 MeSH
- kyseliny hydroxamové MeSH
- molekulární sondy MeSH
- radioizotopy galia MeSH
- receptor cholecystokininu B MeSH
- železité sloučeniny MeSH
The biological behaviour of complexes of 99mTc with aminopolycarboxylic and aminocarbohydroxamic ligands EDTA (ethylenediaminetetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EDTAH (ethylenediaminetetraacetohydroxamic acid) and HIDAmH (N-2-hydroxyethyl-N-carboxymethyl-aminoacetohydroxamic acid) was studied in rabbits. The pharmacokinetic parameters determined in intact rabbits were compared with the results obtained in the study of renal and hepatic clearance of the complexes under study. Hepatobiliary excretion, which in [99mTc]EDTA forms 20-30% of the total excreted amount, is of negligible magnitude in the other 99mTc-complexes studied (less than 2%). Their renal clearance is not influenced by the inhibition of tubular secretion with probenecid. Binding to plasma proteins increases in the order [99mTc]DTPA less than [99mTc]EDTA less than [99mTc]HIDAmH less than [99mTc]EDTAH and the elimination half-life increases in the same order. The value of renal clearance of the complexes studied related to inulin clearance correlates well with the fraction of the free drug in the plasma. In rabbits the complexes under study are excreted mainly by the mechanism of glomerular filtration in the kidney.
- MeSH
- EDTA metabolismus farmakokinetika MeSH
- játra metabolismus MeSH
- králíci MeSH
- kyselina pentetová metabolismus farmakokinetika MeSH
- kyseliny hydroxamové metabolismus farmakokinetika MeSH
- ledviny metabolismus MeSH
- organotechneciové sloučeniny metabolismus farmakokinetika MeSH
- technecium 99mTc pentetát MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Názvy látek
- EDTA MeSH
- kyselina pentetová MeSH
- kyseliny hydroxamové MeSH
- organotechneciové sloučeniny MeSH
- technecium 99mTc pentetát MeSH
- technetium Tc 99m EDTA MeSH Prohlížeč
- technetium Tc 99m ethylenediaminetetraacetohydroxamic acid MeSH Prohlížeč
- technetium Tc 99m N-2-hydroxyethyl-N-carboxymethylaminoacetohydroxamic acid MeSH Prohlížeč
