Tumor uptake of copper-diacetyl-bis(N(4)-methylthiosemicarbazone): effect of changes in tissue oxygenation.

Abstract

UNLABELLED:

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.

CONCLUSION:

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.

• Authors: J S Lewis, T L Sharp, R Laforest, Y Fujibayashi, M J Welch
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 42 Issue 4 Pg. 655-61 (Apr 2001) ISSN: 0161-5505 [Print] United States
• PMID: 11337556 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Coordination Complexes
• Copper Radioisotopes
• Organometallic Compounds
• Radiopharmaceuticals
• Thiosemicarbazones
• copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)
• Hydralazine
• Oxygen

Topics

• Animals
• Autoradiography
• Coordination Complexes
• Copper Radioisotopes (pharmacokinetics)
• Female
• Gliosarcoma (diagnostic imaging, metabolism)
• Hydralazine (pharmacology)
• Neoplasm Transplantation
• Organometallic Compounds (pharmacokinetics)
• Oxygen (analysis)
• Radiopharmaceuticals (pharmacokinetics)
• Rats
• Rats, Inbred F344
• Thiosemicarbazones (pharmacokinetics)
• Tomography, Emission-Computed