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

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State: Public
Version: author
Serval ID
serval:BIB_B76ABFBA19FC
Type
Article: article from journal or magazin.
Collection
Publications
Title
Important Role of CYP2J2 in Protein Kinase Inhibitor Degradation: A Possible Role in Intratumor Drug Disposition and Resistance.
Journal
Plos One
Author(s)
Narjoz C., Favre A., McMullen J., Kiehl P., Montemurro M., Figg W.D., Beaune P., de Waziers I., Rochat B.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Publication state
Published
Issued date
2014
Peer-reviewed
Oui
Volume
9
Number
5
Pages
e95532
Language
english
Notes
Publication types: Journal Article Publication Status: epublish
Abstract
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.
Pubmed
Web of science
Open Access
Yes
Create date
28/06/2014 15:12
Last modification date
20/08/2019 15:25
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