Carboxypeptidase-G 2 Rescue in Cancer Patients with Delayed Methotrexate Elimination after High-dose Methotrexate Therapy

Krause, Anke; Weihrauch, Martin R.; Bode, Udo; Fleischhack, Gudrun; Elter, Thomas; Heuer, T.; Engert, Andreas; Diehl, Volker; Josting, Andreas

doi:10.1080/1042819021000032953

Cited by 38 publications

(38 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, hepatotoxicity and need for dialysis were rare in our cohort compared to what is reported. All patients in our study achieved renal recovery, which is in accordance with the results reported in other studies . In summary, it appears that Mtx‐associated toxicities are less common in children than in adult patients.…”

Section: Discussionsupporting

confidence: 92%

Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia

Svahn

Mellgren

Harila‐Saari

et al. 2016

Pediatr Blood Cancer

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 92%

Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia

Svahn

Mellgren

Harila‐Saari

et al. 2016

Pediatr Blood Cancer

View full text Add to dashboard Cite

show abstract

“…5 However, there is still considerable interpatient variability in clearance of HD MTX with severe delayed MTX clearance seen in 0.5-1% of pediatric patients with ALL, 6,7 1.8% of courses of 12 g/m 2 over 4 hours in youths with OS, 4 and 1-12% of adults treated for lymphoma. 8,9 Patients with delayed MTX clearance are at an increased risk for severe nephrotoxicity, which further reduces MTX elimination and can culminate in life-threatening systemic MTX exposure.…”

Section: Mtxpkorg: a Clinical Decision Support Tool Evaluating High-mentioning

confidence: 99%

MTXPK.org: A Clinical Decision Support Tool Evaluating High‐Dose Methotrexate Pharmacokinetics to Inform Post‐Infusion Care and Use of Glucarpidase

Taylor

Mizuno

Punt³

et al. 2020

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Methotrexate (MTX), an antifolate, is administered at high doses to treat malignancies in children and adults. However, there is considerable interpatient variability in clearance of high‐dose (HD) MTX. Patients with delayed clearance are at an increased risk for severe nephrotoxicity and life‐threatening systemic MTX exposure. Glucarpidase is a rescue agent for severe MTX toxicity that reduces plasma MTX levels via hydrolysis of MTX into inactive metabolites, but is only indicated when MTX concentrations are > 2 SDs above the mean excretion curve specific for the given dose together with a significant creatinine increase (> 50%). Appropriate administration of glucarpidase is challenging due to the ambiguity in the labeled indication. A recent consensus guideline was published with an algorithm to provide clarity in when to administer glucarpidase, yet clinical interpretation of laboratory results that do not directly correspond to the algorithm prove to be a limitation of its use. The goal of our study was to develop a clinical decision support tool to optimize the administration of glucarpidase for patients receiving HD MTX. Here, we describe the development of a novel 3‐compartment MTX population pharmacokinetic (PK) model using 31,672 MTX plasma concentrations from 772 pediatric patients receiving HD MTX for the treatment of acute lymphoblastic leukemia and its integration into the online clinical decision support tool, MTXPK.org. This web‐based tool has the functionality to utilize individualized demographics, serum creatinine, and real‐time drug concentrations to predict the elimination profile and facilitate model‐informed administration of glucarpidase.

show abstract

“…Helicobacter pylori succinyldiaminopimelate desuccinylase is considered a potential target of antimicrobial agents (20), and Pseudomonas sp. strain RS-16 carboxypeptidase G 2 (CPG 2 ) has been proposed for use in antibody-directed enzyme prodrug therapy for the development of a rescue agent in cases of methotrexate overdoses (21)(22)(23)(24)(25).…”

mentioning

confidence: 99%

Crystal Structure and Mutational Analysis of Aminoacylhistidine Dipeptidase from Vibrio alginolyticus Reveal a New Architecture of M20 Metallopeptidases

Chang

Hsieh

Wang

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Aminoacylhistidine dipeptidases (PepD, EC 3.4.13.3) belong to the family of M20 metallopeptidases from the metallopeptidase H clan that catalyze a broad range of dipeptide and tripeptide substrates, including L-carnosine and L-homocarnosine. Homocarnosine has been suggested as a precursor for the neurotransmitter ␥-aminobutyric acid (GABA) and may mediate the antiseizure effects of GABAergic therapies. Here, we report the crystal structure of PepD from Vibrio alginolyticus and the results of mutational analysis of substrate-binding residues in the C-terminal as well as substrate specificity of the PepD catalytic domain-alone truncated protein PepD CAT . The structure of PepD was found to exist as a homodimer, in which each monomer comprises a catalytic domain containing two zinc ions at the active site center for its hydrolytic function and a lid domain utilizing hydrogen bonds between helices to form the dimer interface. Although the PepD is structurally similar to PepV, which exists as a monomer, putative substrate-binding residues reside in different topological regions of the polypeptide chain. In addition, the lid domain of the PepD contains an "extra" domain not observed in related M20 family metallopeptidases with a dimeric structure. Mutational assays confirmed both the putative di-zinc allocations and the architecture of substrate recognition. In addition, the catalytic domain-alone truncated PepD CAT exhibited substrate specificity to L-homocarnosine compared with that of the wild-type PepD, indicating a potential value in applications of PepD CAT for GABAergic therapies or neuroprotection.

show abstract

Carboxypeptidase-G 2 Rescue in Cancer Patients with Delayed Methotrexate Elimination after High-dose Methotrexate Therapy

Cited by 38 publications

References 21 publications

Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia

Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia

MTXPK.org: A Clinical Decision Support Tool Evaluating High‐Dose Methotrexate Pharmacokinetics to Inform Post‐Infusion Care and Use of Glucarpidase

Crystal Structure and Mutational Analysis of Aminoacylhistidine Dipeptidase from Vibrio alginolyticus Reveal a New Architecture of M20 Metallopeptidases

Contact Info

Product

Resources

About