Imaging CXCR4 Expression in Human Cancer Xenografts: Evaluation of Monocyclam 64Cu-AMD3465

被引:72
作者
De Silva, Ravindra A. [1 ]
Peyre, Kevin [1 ]
Pullambhatla, Mrudula [1 ]
Fox, James J. [1 ]
Pomper, Martin G. [1 ]
Nimmagadda, Sridhar [1 ]
机构
[1] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA
关键词
PET; tumor microenvironment; chemokine; stem cells; molecular imaging; colon cancer; brain cancer; metastasis; CHEMOKINE RECEPTOR CXCR4; SMALL-MOLECULE ANTAGONIST; BREAST-CANCER; TUMOR-GROWTH; BINDING; PHARMACOLOGY; INHIBITION; CHEMISTRY; CARCINOMA; BICYCLAM;
D O I
10.2967/jnumed.110.085613
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
The chemokine receptor 4 (CXCR4) is overexpressed in several cancers and metastases and as such presents an enticing target for molecular imaging of metastases and metastatic potential of the primary tumor. CXCR4-based imaging agents could also be useful for diagnosis, staging, and therapeutic monitoring. Here we evaluated a positron-emitting monocyclam analog, Cu-64-{N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine} (Cu-64-AMD3465), in subcutaneous U87 brain tumors and U87 tumors stably expressing CXCR4 (U87-stb-CXCR4) and in colon tumors (HT-29) using dynamic and whole-body PET supported by ex vivo biodistribution studies. Both dynamic and whole-body PET/CT studies show specific accumulation of radioactivity in U87-stb-CXCR4 tumors, with the percentage injected dose per gram reaching a maximum of 102.70 +/- 20.80 at 60 min and tumor-to-muscle ratios reaching a maximum of 362.56 +/- 153.51 at 90 min after injection of the radiotracer. Similar specificity was also observed in the HT-29 colon tumor model. Treatment with AMD3465 inhibited uptake of radioactivity by the tumors in both models. Our results show that Cu-64-AMD3465 is capable of detecting lesions in a CXCR4-dependent fashion, with high target selectivity, and may offer a scaffold for the synthesis of clinically translatable agents.
引用
收藏
页码:986 / 993
页数:8
相关论文
共 41 条
[1]   HIV coreceptor downregulation as antiviral principle: SDF-1 alpha-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication [J].
Amara, A ;
LeGall, S ;
Schwartz, O ;
Salamero, J ;
Montes, M ;
Loetscher, P ;
Baggiolini, M ;
Virelizier, JL ;
ArenzanaSeisdedos, F .
JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 186 (01) :139-146
[2]   The significance of cancer cell expression of the chemokine receptor CXCR4 [J].
Balkwill, F .
SEMINARS IN CANCER BIOLOGY, 2004, 14 (03) :171-179
[3]  
Bjorndal A, 1997, J VIROL, V71, P7478
[4]   Pharmacology of AMD3465: A small molecule antagonist of the chemokine receptor CXCR4 [J].
Bodart, Veronique ;
Anastassov, Virginia ;
Darkes, Marilyn C. ;
Idzan, Stefan R. ;
Labrecque, Jean ;
Lau, Gloria ;
Mosi, Renee M. ;
Neff, Kathleen S. ;
Nelson, Kim L. ;
Ruzek, Melanie C. ;
Patel, Ketan ;
Santucci, Zefferino ;
Scarborough, Robert ;
Wong, Rebecca S. Y. ;
Bridger, Gary J. ;
MacFarland, Ron T. ;
Fricker, Simon P. .
BIOCHEMICAL PHARMACOLOGY, 2009, 78 (08) :993-1000
[5]   Comparative in vivo stability of copper-64-labeled cross-bridged and conventional tetraazamacrocyclic complexes [J].
Boswell, CA ;
Sun, XK ;
Niu, WJ ;
Weisman, GR ;
Wong, EH ;
Rheingold, AL ;
Anderson, CJ .
JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (06) :1465-1474
[6]   CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment [J].
Burger, JA ;
Kipps, TJ .
BLOOD, 2006, 107 (05) :1761-1767
[7]   Targeting the CXCR4/CXCL12 axis in systemic lupus erythematosus [J].
Chong, Benjamin F. ;
Mohan, Chandra .
EXPERT OPINION ON THERAPEUTIC TARGETS, 2009, 13 (10) :1147-1153
[8]   Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis [J].
Darash-Yahana, M ;
Pikarsky, E ;
Abramovitch, R ;
Zeira, E ;
Pal, B ;
Karplus, R ;
Beider, K ;
Avniel, S ;
Kasem, S ;
Galun, E ;
Peled, A .
FASEB JOURNAL, 2004, 18 (09) :1240-+
[9]   Autocrine Induction of Invasive and Metastatic Phenotypes by the MIF-CXCR4 Axis in Drug-Resistant Human Colon Cancer Cells [J].
Dessein, Anne-Frederique ;
Stechly, Laurence ;
Jonckheere, Nicolas ;
Dumont, Patrick ;
Monte, Didier ;
Leteurtre, Emmanuelle ;
Truant, Stephanie ;
Pruvot, Francois-Rene ;
Figeac, Martin ;
Hebbar, Mohamed ;
Lecellier, Charles-Henri ;
Lesuffleur, Thecla ;
Dessein, Rodrigue ;
Grard, Georges ;
Dejonghe, Marie-Jose ;
de Launoit, Yvan ;
Furuichi, Yasuhiro ;
Prevost, Gregoire ;
Porchet, Nicole ;
Gespach, Christian ;
Huet, Guillemette .
CANCER RESEARCH, 2010, 70 (11) :4644-4654
[10]   HIV-1 Entry Cofactor: Functional cDNA Cloing of a Seven-Transmembrane, G protein-Coupled Receptor [J].
Feng, Yu ;
Broder, Christopher C. ;
Kennedy, Paul E. ;
Berger, Edward A. .
JOURNAL OF IMMUNOLOGY, 2011, 186 (11) :872-877