An imaging comparison of 64Cu-ATSM and 60Cu-ATSM in cancer of the uterine cervix.
Tumor uptake of copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone) (copper-ATSM), a hypoxia-targeting radiopharmaceutical, assessed by PET has been found to correlate with prognosis in several human cancers. Wide clinical utility of this tracer will require its labeling with a copper radionuclide having a longer half-life than the (60)Cu used in studies to date. The purpose of this work was to obtain the requisite preclinical data for copper-ATSM to file an investigational new drug application, followed by a crossover comparison of PET image quality and tumor uptake with (60)Cu-ATSM and (64)Cu-ATSM in women with cancer of the uterine cervix.


METHODS
The preclinical toxicology and pharmacology of a copper-ATSM formulation was examined using standard in vitro and in vivo assays, as well as 14-d toxicity studies in both rats and rabbits. For the clinical test-retest imaging study, 10 patients with cervical carcinoma underwent PET on separate days with (60)Cu-ATSM and (64)Cu-ATSM. Image quality was assessed qualitatively, and the tumor-to-muscle activity ratio was measured for each tracer.


RESULTS
The toxicology and pharmacology data demonstrated that the formulation has an appropriate margin of safety for clinical use. In the patient study, we found that the image quality with (64)Cu-ATSM was better than that with (60)Cu-ATSM because of lower noise. In addition, we found that the pattern and magnitude of tumor uptake of (60)Cu-ATSM and (64)Cu-ATSM on studies separated by 1-9 d were similar.


CONCLUSIONS
(64)Cu-ATSM appears to be a safe radiopharmaceutical that can be used to obtain high-quality images of tumor hypoxia in human cancers.
Division of Radiological Sciences, Mallinckrodt Institute of Radiology, St. Louis, Missouri, USA. lewisj2@mskcc.org
Jason S
JS
Lewis
Richard
R
Laforest
Farrokh
F
Dehdashti
Perry W
PW
Grigsby
Michael J
MJ
Welch
Barry A
BA
Siegel
D000328:Adult; D000368:Aged; D000818:Animals; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D008875:Middle Aged; D009942:Organometallic Compounds / Q000633:toxicity; D019047:Phantoms, Imaging; D049268:Positron-Emission Tomography / Q000379:methods; D011817:Rabbits; D019275:Radiopharmaceuticals / Q000633:toxicity; D051381:Rats; D013882:Thiosemicarbazones / Q000633:toxicity; D002583:Uterine Cervical Neoplasms / Q000000981:diagnostic imaging*
D056831:Coordination Complexes; D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)