Titre

Important Role of CYP2J2 in Protein Kinase Inhibitor Degradation: A Possible Role in Intratumor Drug Disposition and Resistance.

Type
article
Institution
Externe
Périodique
Auteur(s)
Narjoz, C.
Auteure/Auteur
Favre, A.
Auteure/Auteur
McMullen, J.
Auteure/Auteur
Kiehl, P.
Auteure/Auteur
Montemurro, M.
Auteure/Auteur
Figg, W.D.
Auteure/Auteur
Beaune, P.
Auteure/Auteur
de Waziers, I.
Auteure/Auteur
Rochat, B.
Auteure/Auteur
Liens vers les personnes
ISSN
1932-6203
Statut éditorial
Publié
Date de publication
2014
Volume
9
Numéro
5
Première page
e95532
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article Publication Status: epublish
Résumé
We have investigated in vitro the metabolic capability of 3 extrahepatic cytochromes P-450, CYP1A1, 1B1 and 2J2, known to be over-expressed in various tumors, to biotransform 5 tyrosine kinase inhibitors (TKI): dasatinib, imatinib, nilotinib, sorafenib and sunitinib. Moreover, mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in 6 hepatocellular and 14 renal cell carcinoma tumor tissues and their surrounding healthy tissues, was determined. Our results show that CYP1A1, 1B1 and especially 2J2 can rapidly biotransform the studied TKIs with a metabolic efficiency similar to that of CYP3A4. The mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in tumor biopsies has shown i) the strong variability of CYP expression and ii) distinct outliers showing high expression levels (esp. CYP2J2) that are compatible with high intratumoral CYP activity and tumor-specific TKI degradation. CYP2J2 inhibition could be a novel clinical strategy to specifically increase the intratumoral rather than plasma TKI levels, improving TKI efficacy and extending the duration before relapse. Such an approach would be akin to beta-lactamase inhibition, a classical strategy to avoid antibiotic degradation and resistance.
PID Serval
serval:BIB_B76ABFBA19FC
DOI
PMID
WOS
Permalien
Open Access
Oui
Date de création
2014-06-28T14:12:57.392Z
Date de création dans IRIS
2025-05-20T21:47:05Z
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