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.

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    • "Moreover, blood flow imaging has the potential to improve hypoxia quantitation by providing a means to compensate for heterogeneous delivery of the hypoxia tracer to different tissues. Copper-pyruvaldehyde- bis[N 4 -methylthiosemicarbazone] (PTSM) (Mathias et al. 1991; Mathias et al. 1994; Flower et al. 2001) and Cu-diacetyl-bis[N 4 -methylthiosemicarbazone] (ATSM) (Fujibayashi et al. 1997; Lewis et al. 1999; Takahashi et al. 2000; Lewis et al. 2001; Dehdashti et al. 2003) are chemical analogues that trace tumor blood flow and hypoxia, respectively. While PTSM distributes in proportion to blood flow and is rapidly reduced and trapped in tissues, ATSM has a lower redox potential and is selectively retained in hypoxic tissues. "
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    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
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    • "Thiosemicarbazone copper complexes have shown interesting anti-proliferative activity in vitro and in vivo [1] [2]. Various radiocopper thiosemicarbazones have been developed for creating possible radiopharmaceuticals as well as tracers with great interest in nuclear medicine and some have already demonstrated putative application in clinical studies, such as Cu-ATSM, accumulating avidly in hypoxic cells [3] [4] and Cu-PTSM as a blood perfusion among tumors as well as vital organs [5] [6]. "
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    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.
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    • "One example is Cu-diacetyl-bis(N 4 -methylthiosemicarbazone ) (Cu-ATSM, Fig. 1). Cu-ATSM has been examined as a possible imaging agent to delineate hypoxic areas within tumors [8] [9]. Cu-ATSM has a suitable molecular size and lipophilicity for penetrating tumor cells, and is selectively reduced and retained under hypoxic conditions [5] [20]. "
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    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
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