Retention of the radiotracers 64Cu-ATSM and 64Cu-PTSM in human and murine tumors is influenced by MDR1 protein expression

Jun Liu, Asghar Hajibeigi, Gang Ren, Mai Lin, Wasana Siyambalapitiyage, Zhisu Liu, Evan Simpson, Robert W. Parkey, Xiankai Sun, Orhan K. Öz

Research output: Contribution to journalArticle

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Abstract

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 inmouse 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.

Original languageEnglish (US)
Pages (from-to)1332-1339
Number of pages8
JournalJournal of Nuclear Medicine
Volume50
Issue number8
DOIs
StatePublished - Aug 1 2009

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Pyruvaldehyde
Multiple Drug Resistance
P-Glycoprotein
Aromatase
Neoplasms
Liver
Knockout Mice
Diacetyl
Cell Line
Tumor Cell Line
Drug Resistance
Heterografts
Nude Mice
Sarcoma
Small Interfering RNA
Real-Time Polymerase Chain Reaction
Glycoproteins
Carrier Proteins
Adenosine Triphosphate

Keywords

  • Copper-diacetyl-bis(N4- methylthiosemicarbazone)
  • Copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone)
  • Hypoxia imaging
  • MDR1
  • P-glycoprotein (Pgp)

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Retention of the radiotracers 64Cu-ATSM and 64Cu-PTSM in human and murine tumors is influenced by MDR1 protein expression. / Liu, Jun; Hajibeigi, Asghar; Ren, Gang; Lin, Mai; Siyambalapitiyage, Wasana; Liu, Zhisu; Simpson, Evan; Parkey, Robert W.; Sun, Xiankai; Öz, Orhan K.

In: Journal of Nuclear Medicine, Vol. 50, No. 8, 01.08.2009, p. 1332-1339.

Research output: Contribution to journalArticle

Liu, Jun ; Hajibeigi, Asghar ; Ren, Gang ; Lin, Mai ; Siyambalapitiyage, Wasana ; Liu, Zhisu ; Simpson, Evan ; Parkey, Robert W. ; Sun, Xiankai ; Öz, Orhan K. / Retention of the radiotracers 64Cu-ATSM and 64Cu-PTSM in human and murine tumors is influenced by MDR1 protein expression. In: Journal of Nuclear Medicine. 2009 ; Vol. 50, No. 8. pp. 1332-1339.
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abstract = "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 inmouse 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.",
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TY - JOUR

T1 - Retention of the radiotracers 64Cu-ATSM and 64Cu-PTSM in human and murine tumors is influenced by MDR1 protein expression

AU - Liu, Jun

AU - Hajibeigi, Asghar

AU - Ren, Gang

AU - Lin, Mai

AU - Siyambalapitiyage, Wasana

AU - Liu, Zhisu

AU - Simpson, Evan

AU - Parkey, Robert W.

AU - Sun, Xiankai

AU - Öz, Orhan K.

PY - 2009/8/1

Y1 - 2009/8/1

N2 - 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 inmouse 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.

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 inmouse 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.

KW - Copper-diacetyl-bis(N4- methylthiosemicarbazone)

KW - Copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone)

KW - Hypoxia imaging

KW - MDR1

KW - P-glycoprotein (Pgp)

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