Abstract
Copper-64 (T1/2 = 12.7 h; β+, 17.4%; β−, 39%) has been used both in positron emission tomography imaging and in radiotherapy. Copper-64 radiopharmaceuticals have shown tumor growth inhibition with a relatively low radiation dose in animal models; however, the mechanism of cytotoxicity has not been fully elucidated. These studies incorporate the use of somatostatin receptor-positive AR42J rat pancreatic tumor cells in vitro to understand the cell killing mechanism of 64Cu by focusing on subcellular distribution of the somatostatin analogues 64Cu-labeled 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide (64Cu-TETA-OC) and 111In-labeled diethylenetriaminepentaacetic acid-octreotide (111In-DTPA-OC). Cell uptake and organelle isolation studies were conducted on 64Cu-TETA-OC and 111In-DTPA-OC. Nuclear localization of 64Cu and 111In from 64Cu-TETA-OC and 111In-DTPA-OC, respectively, increased over time, with 19.5 ± 1.4% and 6.0 ± 1.0% in the cell nucleus at 24 h, respectively. In pulse-chase experiments, in which 64Cu-TETA-OC was incubated with AR42J cells for 4 h, it was found that the nuclear localization of 64Cu increased significantly over the next 20 h (from 9.8 ± 1.0% to 26.3 ± 5.4%). In a control pulse-chase experiment, levels of 64Cu from [64Cu]cupric acetate decreased from 4 to 24 h postadministration (20.6 ± 8.7 to 5.4 ± 1.9), suggesting that the redistribution mechanism, or the kinetics of 64Cu from 64Cu-TETA-OC is different from that for 64Cu from [64Cu]cupric acetate. The amount of 64Cu from 64Cu-TETA-OC also increased in the mitochondria over time, with 21.1 ± 3.6% in the mitochondria at 24 h postadministration. These results suggest that localization of substantial quantities of 64Cu to the cell nucleus and mitochondria may contribute to cell killing with 64Cu radiopharmaceuticals.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 Supported by National Cancer Institute Grant R01 CA64475 and in part by Department of Energy Training Grant DE F0101 NE23051 (to A. L. C.). The production of copper radionuclides at Washington University is supported by National Cancer Institute Grant R24 CA86307 (to Dr. Michael J. Welch).
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↵2 Present address: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri-Columbia, Columbia, MO 65211.
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↵3 To whom requests for reprints should be addressed, at Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, Campus Box 8225, St. Louis, MO 63110. Phone: (314) 362-8427; Fax: (314) 362-9940; E-mail: andersoncj{at}mir.wustl.edu
- Received April 25, 2003.
- Revision received July 21, 2003.
- Accepted August 5, 2003.
- ©2003 American Association for Cancer Research.
Volume 63, Issue 20
