RT Journal Article
SR Electronic
T1 Subcellular Localization of Radiolabeled Somatostatin Analogues
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 6864
OP 6869
VO 63
IS 20
A1 Wang, Mu
A1 Caruano, Amy L.
A1 Lewis, Michael R.
A1 Meyer, Laura A.
A1 VanderWaal, Robert P.
A1 Anderson, Carolyn J.
YR 2003
UL http://cancerres.aacrjournals.org/content/63/20/6864.abstract
AB 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. ©2003 American Association for Cancer Research.