Assessment of regional tumor hypoxia using 18F- fluoromisonidazole and 64Cu(II)-diacetyl-bis(N4- methylthiosemicarbazone) positron emission tomography

Comparative study featuring microPET imaging, Po2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models

Joseph A. O'Donoghue, Pat Zanzonico, Andrei Pugachev, Bixiu Wen, Peter Smith-Jones, Shangde Cai, Eva Burnazi, Ronald D. Finn, Paul Burgman, Shutian Ruan, Jason S. Lewis, Michael J. Welch, C. Clifton Ling, John L. Humm

Research output: Contribution to journalArticle

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Abstract

Purpose: To compare two potential positron emission tomography (PET) tracers of tumor hypoxia in an animal model. Methods and Materials: The purported hypoxia imaging agents 18F-fluoromisonidazole (FMISO) and 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) were compared by serial microPET imaging of Fisher-Copenhagen rats bearing the R3327-AT anaplastic rat prostate tumor. Probe measurements of intratumoral Po2 were compared with the image data. At the microscopic level, the relationship between the spatial distributions of 64Cu (assessed by digital autoradiography) and tumor hypoxia (assessed by immunofluorescent detection of pimonidazole) was examined. 18F-FMISO and 64Cu-ATSM microPET images were also acquired in nude rats bearing xenografts derived from the human squamous cell carcinoma cell line, FaDu. Results: In R3327-AT tumors, the intratumoral distribution of 18F-FMISO remained relatively constant 1-4 h after injection. However, that of 64Cu-ATSM displayed a significant temporal evolution for 0.5-20 h after injection in most tumors. In general, only when 64Cu-ATSM was imaged at later times (16-20 h after injection) did it correspond to the distribution of 18F-FMISO. Oxygen probe measurements were broadly consistent with 18F-FMISO and late 64Cu-ATSM images but not with early 64Cu-ATSM images. At the microscopic level, a negative correlation was found between tumor hypoxia and 64Cu distribution when assessed at early times and a positive correlation when assessed at later times. For the FaDu tumor model, the early and late 64Cu-ATSM microPET images were similar and were in general concordance with the 18F-FMISO scans. Conclusion: The difference in behavior between the R3327-AT and FaDu tumor models suggests a tumor-specific dependence of Cu-ATSM uptake and retention under hypoxic conditions.

Original languageEnglish (US)
Pages (from-to)1493-1502
Number of pages10
JournalInternational Journal of Radiation Oncology Biology Physics
Volume61
Issue number5
DOIs
StatePublished - Apr 1 2005
Externally publishedYes

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autoradiography
Diacetyl
hypoxia
Autoradiography
Positron-Emission Tomography
rats
Microscopy
positrons
tumors
tomography
microscopy
probes
Neoplasms
Injections
Nude Rats
injection
Heterografts
fluoromisonidazole
Tumor Hypoxia
Prostate

Keywords

  • Correlative study
  • Hoechst 33342
  • Oxygen probe
  • Pimonidazole
  • Positron emission tomography
  • Tumor hypoxia

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Assessment of regional tumor hypoxia using 18F- fluoromisonidazole and 64Cu(II)-diacetyl-bis(N4- methylthiosemicarbazone) positron emission tomography : Comparative study featuring microPET imaging, Po2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models. / O'Donoghue, Joseph A.; Zanzonico, Pat; Pugachev, Andrei; Wen, Bixiu; Smith-Jones, Peter; Cai, Shangde; Burnazi, Eva; Finn, Ronald D.; Burgman, Paul; Ruan, Shutian; Lewis, Jason S.; Welch, Michael J.; Ling, C. Clifton; Humm, John L.

In: International Journal of Radiation Oncology Biology Physics, Vol. 61, No. 5, 01.04.2005, p. 1493-1502.

Research output: Contribution to journalArticle

O'Donoghue, Joseph A. ; Zanzonico, Pat ; Pugachev, Andrei ; Wen, Bixiu ; Smith-Jones, Peter ; Cai, Shangde ; Burnazi, Eva ; Finn, Ronald D. ; Burgman, Paul ; Ruan, Shutian ; Lewis, Jason S. ; Welch, Michael J. ; Ling, C. Clifton ; Humm, John L. / Assessment of regional tumor hypoxia using 18F- fluoromisonidazole and 64Cu(II)-diacetyl-bis(N4- methylthiosemicarbazone) positron emission tomography : Comparative study featuring microPET imaging, Po2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models. In: International Journal of Radiation Oncology Biology Physics. 2005 ; Vol. 61, No. 5. pp. 1493-1502.
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abstract = "Purpose: To compare two potential positron emission tomography (PET) tracers of tumor hypoxia in an animal model. Methods and Materials: The purported hypoxia imaging agents 18F-fluoromisonidazole (FMISO) and 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) were compared by serial microPET imaging of Fisher-Copenhagen rats bearing the R3327-AT anaplastic rat prostate tumor. Probe measurements of intratumoral Po2 were compared with the image data. At the microscopic level, the relationship between the spatial distributions of 64Cu (assessed by digital autoradiography) and tumor hypoxia (assessed by immunofluorescent detection of pimonidazole) was examined. 18F-FMISO and 64Cu-ATSM microPET images were also acquired in nude rats bearing xenografts derived from the human squamous cell carcinoma cell line, FaDu. Results: In R3327-AT tumors, the intratumoral distribution of 18F-FMISO remained relatively constant 1-4 h after injection. However, that of 64Cu-ATSM displayed a significant temporal evolution for 0.5-20 h after injection in most tumors. In general, only when 64Cu-ATSM was imaged at later times (16-20 h after injection) did it correspond to the distribution of 18F-FMISO. Oxygen probe measurements were broadly consistent with 18F-FMISO and late 64Cu-ATSM images but not with early 64Cu-ATSM images. At the microscopic level, a negative correlation was found between tumor hypoxia and 64Cu distribution when assessed at early times and a positive correlation when assessed at later times. For the FaDu tumor model, the early and late 64Cu-ATSM microPET images were similar and were in general concordance with the 18F-FMISO scans. Conclusion: The difference in behavior between the R3327-AT and FaDu tumor models suggests a tumor-specific dependence of Cu-ATSM uptake and retention under hypoxic conditions.",
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T1 - Assessment of regional tumor hypoxia using 18F- fluoromisonidazole and 64Cu(II)-diacetyl-bis(N4- methylthiosemicarbazone) positron emission tomography

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AU - O'Donoghue, Joseph A.

AU - Zanzonico, Pat

AU - Pugachev, Andrei

AU - Wen, Bixiu

AU - Smith-Jones, Peter

AU - Cai, Shangde

AU - Burnazi, Eva

AU - Finn, Ronald D.

AU - Burgman, Paul

AU - Ruan, Shutian

AU - Lewis, Jason S.

AU - Welch, Michael J.

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AU - Humm, John L.

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N2 - Purpose: To compare two potential positron emission tomography (PET) tracers of tumor hypoxia in an animal model. Methods and Materials: The purported hypoxia imaging agents 18F-fluoromisonidazole (FMISO) and 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) were compared by serial microPET imaging of Fisher-Copenhagen rats bearing the R3327-AT anaplastic rat prostate tumor. Probe measurements of intratumoral Po2 were compared with the image data. At the microscopic level, the relationship between the spatial distributions of 64Cu (assessed by digital autoradiography) and tumor hypoxia (assessed by immunofluorescent detection of pimonidazole) was examined. 18F-FMISO and 64Cu-ATSM microPET images were also acquired in nude rats bearing xenografts derived from the human squamous cell carcinoma cell line, FaDu. Results: In R3327-AT tumors, the intratumoral distribution of 18F-FMISO remained relatively constant 1-4 h after injection. However, that of 64Cu-ATSM displayed a significant temporal evolution for 0.5-20 h after injection in most tumors. In general, only when 64Cu-ATSM was imaged at later times (16-20 h after injection) did it correspond to the distribution of 18F-FMISO. Oxygen probe measurements were broadly consistent with 18F-FMISO and late 64Cu-ATSM images but not with early 64Cu-ATSM images. At the microscopic level, a negative correlation was found between tumor hypoxia and 64Cu distribution when assessed at early times and a positive correlation when assessed at later times. For the FaDu tumor model, the early and late 64Cu-ATSM microPET images were similar and were in general concordance with the 18F-FMISO scans. Conclusion: The difference in behavior between the R3327-AT and FaDu tumor models suggests a tumor-specific dependence of Cu-ATSM uptake and retention under hypoxic conditions.

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KW - Correlative study

KW - Hoechst 33342

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KW - Positron emission tomography

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