Tumor uptake of copper-diacetyl-bis(N(4)-methylthiosemicarbazone): effect of changes in tissue oxygenation.
We showed previously that, in vitro, copper-diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) uptake is dependent on the oxygen concentration (pO2). We also showed that, in vivo, Cu-ATSM uptake is heterogeneous in animal tumors known to contain hypoxic fractions. This study was undertaken to confirm the pO2 dependence of this selective uptake in vivo by correlating Cu-ATSM uptake with measured tumor pO2.


METHODS
Experiments were performed with the 9L gliosarcoma rat model using a needle oxygen electrode to measure tissue pO2. Using PET and electronic autoradiography, Cu-ATSM uptake was measured in tumor tissue under various pO2 levels. The oxygen concentration within implanted tumors was manipulated by chemical means or by altering the inhaled oxygen content.


RESULTS
A good correlation between low pO2 and high Cu-ATSM accumulation was observed. Hydralazine administration in animals caused a decrease in the average tumor pO2 from 28.61 +/- 8.74 mm Hg to 20.81 +/- 7.54 mm Hg in untreated control animals breathing atmospheric oxygen. It also caused the tumor uptake of Cu-ATSM to increase by 35%. Conversely, in animals breathing 100% oxygen, the average tumor pO2 increased to 45.88 +/-15.9 mm Hg, and the tumor uptake of Cu-ATSM decreased to 48% of that of the control animals. PET of animals treated in a similar fashion yielded time-activity curves showing significantly higher retention of the tracer in hypoxic tissues than in oxygenated tissues.


CONCLUSIONS
These data confirm that Cu-ATSM uptake in tissues in vivo is dependent on the tissue pO2, and that significantly greater uptake and retention occur in hypoxic tumor tissue. Therefore, the possible use of Cu-ATSM PET as a prognostic indicator in the management of cancer is further validated.
Lewis
J S
JS
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Sharp
T L
TL
Laforest
R
R
Fujibayashi
Y
Y
Welch
M J
MJ
D000818:Animals; D001345:Autoradiography; D056831:Coordination Complexes; D003301:Copper Radioisotopes / Q000493:pharmacokinetics; D005260:Female; D018316:Gliosarcoma / Q000000981:diagnostic imaging / Q000378:metabolism*; D006830:Hydralazine / Q000494:pharmacology; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D010100:Oxygen / Q000032:analysis*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D013882:Thiosemicarbazones / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed
D056831:Coordination Complexes; D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D006830:Hydralazine; D010100:Oxygen