Article

Tumor Uptake of Copper-Diacetyl-Bis(N4- Methylthiosemicarbazone): Effect of Changes in Tissue Oxygenation

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Journal of Nuclear Medicine (Impact Factor: 5.56). 05/2001; 42(4).

ABSTRACT 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 corre- lating 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 6 8.74 mm Hg to 20.81 6 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 45.88 615.9 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 depen- dent 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 manage- ment of cancer is further validated.

Download full-text

Full-text

Available from: Terry L Sharp, Apr 01, 2014
1 Follower
 · 
45 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Blood flow and hypoxia are interrelated aspects of physiology that affect cancer treatment and response. Cu-PTSM and Cu-ATSM are related PET tracers for blood flow and hypoxia, and the ability to rapidly image both tracers in a single scan would bring several advantages over conventional single-tracer techniques. Using dynamic imaging with staggered injections, overlapping signals for multiple PET tracers may be recovered utilizing information from kinetics and radioactive decay. In this work, rapid dual-tracer PTSM+ATSM PET was simulated and tested as a function of injection delay, order and relative dose for several copper isotopes, and the results were compared relative to separate single-tracer data. Time-activity curves representing a broad range of tumour blood flow and hypoxia levels were simulated, and parallel dual-tracer compartment modelling was used to recover the signals for each tracer. The main results were tested further using a torso phantom simulation of PET tumour imaging. Using scans as short as 30 minutes, the dual-tracer method provided measures of blood flow and hypoxia similar to single-tracer imaging. The best performance was obtained by injecting PTSM first and using a somewhat higher dose for ATSM. Comparable results for different copper isotopes suggest that tracer kinetics with staggered injections play a more important role than radioactive decay in the signal separation process. Rapid PTSM+ATSM PET has excellent potential for characterizing both tumour blood flow and hypoxia in a single, fast scan, provided that technological hurdles related to algorithm development and routine use can be overcome.
    Physics in Medicine and Biology 02/2006; 51(1):61-75. DOI:10.1088/0031-9155/51/1/005 · 2.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 61 Cu]-N-(2-hydroxyacetophenone)glycinate ([ 61 Cu]NHAG) was prepared using in house-made NHAG ligand and [ 61 Cu]CuCl 2 produced via the nat Zn(p,x) 61 Cu (180μA proton irradiation, 22MeV, 3.2h) and purified by a ion chromatography method. [ 61 Cu]NHAG radiochemical purity was >98% and >99.9% by RTLC and HPLC methods respectively after purification by SPE. [ 61 Cu]NHAG was administered into normal and tumor bearing mice followed by biodistribution studies up to 180 minutes. The best tumor accumulation was observed by animal sacrification after 120 min (tumor/muscle and tumor/blood ratios were 25.6 and 3.4 respectively). [ 61 Cu]NHAG is a potential PET radiotracer for tumor imaging.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: (64)Cu-labeled diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) is a promising agent for internal radiation therapy and imaging of hypoxic tissues. In the present study, the intra-tumoral distribution of (64)Cu-ATSM was investigated by comparing it to that of [(18)F]FDG and histological findings. VX2 tumors were implanted into Japanese white rabbits subcutaneously. (64)Cu-ATSM and [(18)F]FDG were co-injected intravenously and the tumor was dissected and cut into 1 mm thick slices 1 h after the injection. The uptake of (64)Cu-ATSM and [(18)F]FDG was measured using a dual-tracer autoradiographic technique. Histological cell biology was estimated from the optical microscopy of tumor sections. The major accumulation of (64)Cu-ATSM was observed around the outer rim of the tumor masses which consisted mainly of active cells and expected to be hypoxic. [(18)F]FDG was distributed more widely with highest levels in the inner regions where pre-necrotic cells were mainly observed. (64)Cu-ATSM appears to be useful for the detection of hypoxic but active tumor cell regions in vivo.
    Nuclear Medicine and Biology 08/2003; 30(5):529-34. DOI:10.1016/S0969-8051(03)00047-7 · 2.41 Impact Factor