Article

Assessing tumor hypoxia by positron emission tomography with Cu-ATSM

Radiochemistry Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
The quarterly journal of nuclear medicine and molecular imaging: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of... (Impact Factor: 2.03). 07/2009; 53(2):193-200.
Source: PubMed

ABSTRACT

For the last several decades, hypoxia has been recognized to be one of the key factors in tumor aggression and an important impediment to local and distant control of malignant tumors. In addition, hypoxia is a major cause of failure of both radiation therapy and chemotherapy. It has been shown that hypoxia is an independent negative prognostic factor for patient outcome in various solid tumors. Clinical studies using polarographic oxygen electrodes, as a tool for measuring hypoxia, were the first to demonstrate the presence of hypoxia in human tumors and its association with poor prognosis. However, this method is invasive and has technical limitations that prevent its routine clinical use. Over the years, imaging as a noninvasive method has attracted a lot of attention and several radiotracers have been developed for noninvasive evaluation of hypoxia. One of the most promising radiotracers is the copper(II) complex of diacetyl-2,3-bis(N(4)-methyl-3-thiosemicarbazonato) ligand (Cu-ATSM) for imaging with positron emission tomography. In this review, the preclinical evaluation of Cu-ATSM as well as its clinical value in several solid tumors will be discussed.

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    • "The proposed trapping mechanism of Cu-ATSM is indirectly linked to hypoxia, via chemical reduction from a cell membrane permeable to a non-permeable state. The exact mechanism by which Cu-ATSM is trapped in hypoxic cells or the oxygen-level required for accumulation is however not completely understood [7,8]. "
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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.
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    ABSTRACT: The purpose of this study was to delineate the differences in intratumoral uptake and tracer distribution of (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) ((62)Cu-ATSM), a well-known hypoxic imaging tracer, and (18)F-FDG in patients with lung cancer of pathohistologically different types. Eight patients with squamous cell carcinoma (SCC) and 5 with adenocarcinoma underwent (62)Cu-ATSM and (18)F-FDG PET within a 1-wk interval. For (62)Cu-ATSM PET, 10-min static data acquisition was started at 10 min after a 370- to 740-MBq tracer injection. After image reconstruction, (62)Cu-ATSM and (18)F-FDG images were coregistered, and multiple small regions of interest were drawn on tumor lesions of the 2 images to obtain standardized uptake values (SUVs). The regression lines were determined between SUVs for (62)Cu-ATSM and (18)F-FDG in each tumor. The slope values were compared between SCC and adenocarcinoma to observe pathohistologic differences in intratumoral distribution of the tracers. SUVs for (62)Cu-ATSM were lower than those for (18)F-FDG in both SCC and adenocarcinoma. SCC tumors showed high (62)Cu-ATSM and low (18)F-FDG uptakes in the peripheral region of tumors but low (62)Cu-ATSM and high (18)F-FDG uptakes toward the center (spatial mismatching). The relationship of SUVs for the 2 tracers was negatively correlated with a mean regression slope of -0.07 +/- 0.05. On the other hand, adenocarcinoma tumors had a spatially similar distribution of (62)Cu-ATSM and (18)F-FDG, with positive regression slopes averaging 0.24 +/- 0.13. The regression slopes for (62)Cu-ATSM and (18)F-FDG differed significantly between SCC and adenocarcinoma (P < 0.001). The intratumoral distribution patterns of (62)Cu-ATSM and (18)F-FDG were different between SCC and adenocarcinoma in lung cancers, indicating that intratumoral regions of high glucose metabolism and hypoxia could differ with the pathohistologic type of lung cancer. The identification of regional biologic characteristics in tumors such as hypoxia, energy metabolism, and proliferation could play a significant role in the clinical diagnosis and therapy planning for non-small cell lung cancer patients.
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