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.
OBJECTIVE
To compare two potential positron emission tomography (PET) tracers of tumor hypoxia in an animal model.


METHODS
The purported hypoxia imaging agents (18)F-fluoromisonidazole (FMISO) and (64)Cu(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 Po(2) were compared with the image data. At the microscopic level, the relationship between the spatial distributions of (64)Cu (assessed by digital autoradiography) and tumor hypoxia (assessed by immunofluorescent detection of pimonidazole) was examined. (18)F-FMISO and (64)Cu-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 (18)F-FMISO remained relatively constant 1-4 h after injection. However, that of (64)Cu-ATSM displayed a significant temporal evolution for 0.5-20 h after injection in most tumors. In general, only when (64)Cu-ATSM was imaged at later times (16-20 h after injection) did it correspond to the distribution of (18)F-FMISO. Oxygen probe measurements were broadly consistent with (18)F-FMISO and late (64)Cu-ATSM images but not with early (64)Cu-ATSM images. At the microscopic level, a negative correlation was found between tumor hypoxia and (64)Cu distribution when assessed at early times and a positive correlation when assessed at later times. For the FaDu tumor model, the early and late (64)Cu-ATSM microPET images were similar and were in general concordance with the (18)F-FMISO scans.


CONCLUSIONS
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.
O'Donoghue
Joseph A
JA
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. odonoghj@mskcc.org
Zanzonico
Pat
P
Pugachev
Andrei
A
Wen
Bixiu
B
Smith-Jones
Peter
P
Cai
Shangde
S
Burnazi
Eva
E
Finn
Ronald D
RD
Burgman
Paul
P
Ruan
Shutian
S
Lewis
Jason S
JS
Welch
Michael J
MJ
Ling
C Clifton
CC
Humm
John L
JL
D000818:Animals; D001345:Autoradiography; D001562:Benzimidazoles; D015687:Cell Hypoxia; D056831:Coordination Complexes; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008856:Microscopy, Fluorescence; D008920:Misonidazole / Q000031:analogs & derivatives*; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000503:physiopathology*; D009593:Nitroimidazoles / Q000032:analysis; D009942:Organometallic Compounds; D049268:Positron-Emission Tomography / Q000379:methods*; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; D051381:Rats; D011923:Rats, Nude; D013882:Thiosemicarbazones; D014183:Transplantation, Heterologous
D001562:Benzimidazoles; D056831:Coordination Complexes; D009593:Nitroimidazoles; D009942:Organometallic Compounds; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); C031843:fluoromisonidazole; D019788:Fluorodeoxyglucose F18; C033815:pimonidazole; D008920:Misonidazole; C017807:bisbenzimide ethoxide trihydrochloride