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Noninvasive detection of carboxypeptidase G2 activity in vivo
Author(s) -
Jamin Yann,
Smyth Lynette,
Robinson Simon P.,
Poon Evon S. C.,
Eykyn Thomas R.,
Springer Caroline J.,
Leach Martin O.,
Payne Geoffrey S.
Publication year - 2011
Publication title -
nmr in biomedicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.278
H-Index - 114
eISSN - 1099-1492
pISSN - 0952-3480
DOI - 10.1002/nbm.1597
Subject(s) - prodrug , in vivo , reporter gene , adept , medicine , pharmacology , biochemistry , chemistry , gene expression , biology , gene , microbiology and biotechnology
The pseudomonad protein, carboxypeptidase G2 (CPG2), is a prodrug‐activating enzyme utilized in the targeted chemotherapy strategies of antibody‐ and gene‐directed enzyme prodrug therapy (ADEPT and GDEPT). We have developed a noninvasive imaging approach to monitor CPG2 activity in vivo that will facilitate the preclinical and clinical development of CPG2‐based ADEPT and GDEPT strategies. Cleavage of the novel reporter probe, 3,5‐difluorobenzoyl‐ L ‐glutamic acid (3,5‐DFBGlu), by CPG2, in human colon adenocarcinoma WiDr xenografts engineered to stably express CPG2, was monitored using 19 F MRSI. The high signal‐to‐noise ratio afforded by the two MR‐equivalent 19 F nuclei of 3,5‐DFBGlu, and the 1.4 ppm 19 F chemical shift difference on CPG2‐mediated cleavage, enabled the dynamics and quantification of the apparent pharmacokinetics of 3,5‐DFBGlu and its CPG2‐mediated cleavage in the tumor to be evaluated. In addition, the apparent rate of increase of 3,5‐difluorobenzoic acid concentration could also provide a biomarker of CPG2 activity levels in tumors of patients undergoing CPG2‐based therapies, as well as a biomarker of treatment response. The addition of in vivo reporter probes, such as 3,5‐DFBGlu, to the armamentarium of prodrugs cleaved by CPG2 affords new applications for CPG2 as a gene reporter of transgene expression. Copyright © 2010 John Wiley & Sons, Ltd.