Tumor uptake of copper-diacetyl-bis (n⁴-methylthiosemicarbazone): Effect of changes in tissue oxygenation

We showed previously that, in vitro, copper-diacetyl-bis (N⁴-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.