Copper-64-diacetyl-bis(N(4)-methylthiosemicarbazone) pharmacokinetics in FaDu xenograft tumors and correlation with microscopic markers of hypoxia.
OBJECTIVE
The behavior of copper-64-diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) in hypoxic tumors was examined through a combination of in vivo dynamic positron emission tomography (PET) and ex vivo autoradiographic and histologic evaluation using a xenograft model of head-and-neck squamous cell carcinoma.


METHODS
(64)Cu-ATSM was administered during dynamic PET imaging, and temporal changes in (64)Cu-ATSM distribution within tumors were evaluated for at least 1 hour and up to 18 hours. Animals were sacrificed at either 1 hour (cohort A) or after 18 hours (cohort B) postinjection of radiotracer and autoradiography performed. Ex vivo analysis of microenvironment subregions was conducted by immunohistochemical staining for markers of hypoxia (pimonidazole hydrochloride) and blood flow (Hoechst-33342).


RESULTS
Kinetic analysis revealed rapid uptake of radiotracer by tumors. The net influx (K(i)) constant was 12-fold that of muscle, whereas the distribution volume (V(d)) was 5-fold. PET images showed large tumor-to-muscle ratios, which continually increased over the entire 18-hour course of imaging. However, no spatial changes in (64)Cu-ATSM distribution occurred in PET imaging at 20 minutes postinjection. Microscopic intratumoral distribution of (64)Cu-ATSM and pimonidazole were not correlated at 1 hour or after 18 hours postinjection, nor was (64)Cu-ATSM and Hoechst-33342.


CONCLUSIONS
The oxygen partial pressures at which (64)Cu-ATSM and pimonidazole are reduced and bound in cells are theorized to be distinct and separable. However, this study demonstrated that microscopic distributions of these tracers within tumors are independent. Researchers have shown (64)Cu-ATSM uptake to be specific to malignant expression, and this work has also demonstrated clear tumor targeting by the radiotracer.
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Keisha C
KC
McCall
John L
JL
Humm
Rachel
R
Bartlett
Megan
M
Reese
Sean
S
Carlin
D000818:Animals; D001345:Autoradiography; D015415:Biomarkers / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000378:metabolism*; D015687:Cell Hypoxia; D056831:Coordination Complexes; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D009132:Muscles / Q000000981:diagnostic imaging / Q000378:metabolism; D009593:Nitroimidazoles / Q000378:metabolism; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D010313:Partial Pressure; D011877:Radionuclide Imaging; D051381:Rats; D011923:Rats, Nude; D013882:Thiosemicarbazones / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D015415:Biomarkers; D056831:Coordination Complexes; D009593:Nitroimidazoles; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); C033815:pimonidazole