RT Journal Article
SR Electronic
T1 Retention of the Radiotracers <sup>64</sup>Cu-ATSM and <sup>64</sup>Cu-PTSM in Human and Murine Tumors Is Influenced by MDR1 Protein Expression
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1332
OP 1339
DO 10.2967/jnumed.109.061879
VO 50
IS 8
A1 Jun Liu
A1 Asghar Hajibeigi
A1 Gang Ren
A1 Mai Lin
A1 Wasana Siyambalapitiyage
A1 Zhisu Liu
A1 Evan Simpson
A1 Robert W. Parkey
A1 Xiankai Sun
A1 Orhan K. Öz
YR 2009
UL http://jnm.snmjournals.org/content/50/8/1332.abstract
AB Tumor hypoxia is often associated with resistance to chemotherapy. Multidrug resistance type 1 (MDR1) protein is a member of the adenosine triphosphate binding cassette (ABC) proteins, some of which are involved in the multidrug resistance (MDR) phenotype in tumors. Many studies have focused on the role of these proteins in modulating drug resistance, but their effect on retention of imaging agents is less well studied. To study the role of MDR1 expression on the accumulation of 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) and 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (64Cu-PTSM) in human tumors in vitro and in vivo, we used a model system composed of a low MDR1–expressing parent uterine sarcoma cell line and a daughter cell line selected for overexpression of MDR1. Aromatase knockout (ArKO) mice that spontaneously developed liver tumors were used as an additional in vivo model to study the effect of MDR expression on 64Cu-ATSM and -PTSM retention. Methods: Biodistribution experiments after injection of 64Cu-ATSM or -PTSM were performed in wild-type mice, ArKO mice, and ArKO mice bearing liver tumors (n = 3–5/group), and in nude mice bearing human tumor xenografts for in vivo PET/CT. Liver expression of Abcb1a and Abcb1b, the MDR1 proteins in mouse liver, was determined by real-time polymerase chain reaction. 64Cu-ATSM and -PTSM accumulation and efflux studies were conducted in tumor cell lines. The uptake experiments were repeated after knockdown of MDR1 protein expression using MDR1-specific small interfering RNAs. Results: In vivo, the hepatic tumors had a lower percentage injected dose per gram of 64Cu-ATSM or -PTSM and more highly expressed Abcb1b than did wild-type liver or nontumor-bearing ArKO liver. High MDR1–expressing tumors showed lower tracer activity on PET/CT images. In vitro, cells highly expressing MDR1 had significantly decreased 64Cu-ATSM and -PTSM retention and enhanced efflux. Knockdown of MDR1 expression significantly enhanced the 64Cu-ATSM and -PTSM retention and decreased the efflux in MDR1-positive cells. Conclusion: The expression of MDR1 glycoprotein (or its equivalents in mice) affects the retention of 64Cu-ATSM and -PTSM in the human and murine tumors tested. These results may have implications for clinical hypoxia imaging in tumors and the therapeutic efficacy of 64Cu-ATSM.