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: 6.16). 05/2001; 42(4).


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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Available from: Terry L Sharp, Apr 01, 2014
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    • "64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors [1], [2], [3]. Radiolabeled Cu-ATSM was originally developed as a positron emission tomography (PET) imaging agent for hypoxia [2], [4], [5], [6], [7]. Clinical PET studies with Cu-ATSM have been already performed, and the usefulness of this agent has been recognized; for example, Cu-ATSM uptake correlated with therapeutic resistance and metastatic potential in several tumors, including uterine cervical carcinoma and rectal carcinoma [4], [7], [8]. "
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    ABSTRACT: (64)Cu-diacetyl-bis (N (4)-methylthiosemicarbazone) ((64)Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors related to malignant characteristics. Its diagnostic usefulness has been recognized in clinical studies. Internal radiotherapy (IRT) with (64)Cu-ATSM is reportedly effective in preclinical studies; however, for clinical applications, improvements to reduce radiation exposure in non-target organs, particularly the liver, are required. We developed a strategy to reduce radiation doses to critical organs while preserving tumor radiation doses by controlled administration of copper chelator penicillamine during (64)Cu-ATSM IRT. Biodistribution was evaluated in HT-29 tumor-bearing mice injected with (64)Cu-ATSM (185 kBq) with or without oral penicillamine administration. The appropriate injection interval between (64)Cu-ATSM and penicillamine was determined. Then, the optimal penicillamine administration schedule was selected from single (100, 300, and 500 mg/kg) and fractionated doses (100 mg/kg×3 at 1- or 2-h intervals from 1 h after (64)Cu-ATSM injection). PET imaging was performed to confirm the effect of penicillamine with a therapeutic (64)Cu-ATSM dose (37 MBq). Dosimetry analysis was performed to estimate human absorbed doses. Penicillamine reduced (64)Cu accumulation in the liver and small intestine. Tumor uptake was not affected by penicillamine administration at 1 h after (64)Cu-ATSM injection, when radioactivity was almost cleared from the blood and tumor uptake had plateaued. Of the single doses, 300 mg/kg was most effective. Fractionated administration at 2-h intervals further decreased liver accumulation at later time points. PET indicated that penicillamine acts similarly with the therapeutic (64)Cu-ATSM dose. Dosimetry demonstrated that appropriately scheduled penicillamine administration reduced radiation doses to critical organs (liver, ovaries, and red marrow) below tolerance levels. Laxatives reduced radiation doses to the large intestine. We developed a novel strategy to reduce radiation exposure in critical organs during (64)Cu-ATSM IRT, thus promoting its clinical applications. This method could be beneficial for other (64)Cu-labeled compounds.
    PLoS ONE 01/2014; 9(1):e86996. DOI:10.1371/journal.pone.0086996 · 3.23 Impact Factor
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    • "Varieties of metallic PET and single photon emission computed tomography (SPECT) radionuclides were incorporated into thiosemicarbazones chelates. Among these radionuclides , 67/68 Ga and copper-62/64 ( 62/64 Cu) have shown considerable success for targeting hypoxic and normoxic tumor xenografts in athymic mouse models [12] [13] [14] [15] [16] [17] [18] [19]. "
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    ABSTRACT: In an attempt to develop new tumor imaging radiotracers with favorable biochemical properties, we have synthesized new 68Ga-2-acetylpyridine semicarbazone (68Ga-[APSC]2) as a potential positron emission tomography (PET) tumor imaging agent using a straightforward and a one-step simple reaction. Radiochemical yield and purity were quantitative without HPLC purification. Biodistribution studies in nude mice model bearing human MDA-MB-231 cell line xenografts displayed significant tumor uptake of 68Ga-[APSC]2 radiotracer after 2 h postinjection (p.i.). The initial results demonstrate that 68Ga-[APSC]2 radiotracer may be useful probe for detecting and staging of hypoxic tumor using PET imaging modality.
    01/2014; 2014:1-6. DOI:10.1155/2014/616459
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    • "Invasive and non-invasive preclinical studies of Cu-ATSM have been conducted in xenografted animal models using various cancer lines. Cu-ATSM accumulation was positively correlated to hypoxia as measured by polarographic microelectrodes in a 9 L gliosarcoma rat model [9]. Additional studies have examined the uptake and distribution patterns of Cu-ATSM, to various non-invasive and invasive surrogate markers for hypoxia. "
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    ABSTRACT: The aim of this study was to compare (64)Cu-diacetyl-bis(N(4)-methylsemicarbazone) ((64)Cu-ATSM) and (18)FDG PET uptake characteristics and (64)Cu-ATSM autoradiography to pimonidazole immunohistochemistry in spontaneous canine sarcomas and carcinomas. Biopsies were collected from individual tumors between approximately 3 and 25 hours after the intravenous injection of (64)Cu-ATSM and pimonidazole. (64)Cu-ATSM autoradiography and pimonidazole immunostaining was performed on sectioned biopsies. Acquired (64)Cu-ATSM autoradiography and pimonidazole images were rescaled, aligned and their distribution patterns compared. (64)Cu-ATSM and (18)FDG PET/CT scans were performed in a concurrent study and uptake characteristics were obtained for tumors where available. Maximum pimonidazole pixel value and mean pimonidazole labeled fraction was found to be strongly correlated to (18)FDG PET uptake levels, whereas more varying results were obtained for the comparison to (64)Cu-ATSM. In the case of the latter, uptake at scans performed 3 h post injection (pi) generally showed strong positive correlated to pimonidazole uptake.Comparison of distribution patterns of pimonidazole immunohistochemistry and (64)Cu-ATSM autoradiography yielded varying results. Significant positive correlations were mainly found in sections displaying a heterogeneous distribution of tracers. Tumors with high levels of pimonidazole staining generally displayed high uptake of (18)FDG and (64)Cu-ATSM (3 h pi.). Similar regional distribution of (64)Cu-ATSM and pimonidazole was observed in most heterogeneous tumor regions. However, tumor and hypoxia level dependent differences may exist with regard to the hypoxia specificity of (64)Cu-ATSM in canine tumors.
    Radiation Oncology 06/2012; 7(1):89. DOI:10.1186/1748-717X-7-89 · 2.55 Impact Factor
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