Subcellular localization of radiolabeled somatostatin analogues: implications for targeted radiotherapy of cancer.
Copper-64 (T(1/2) = 12.7 h; beta(+), 17.4%; beta(-), 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 (64)Cu by focusing on subcellular distribution of the somatostatin analogues (64)Cu-labeled 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide ((64)Cu-TETA-OC) and (111)In-labeled diethylenetriaminepentaacetic acid-octreotide ((111)In-DTPA-OC). Cell uptake and organelle isolation studies were conducted on (64)Cu-TETA-OC and (111)In-DTPA-OC. Nuclear localization of (64)Cu and (111)In from (64)Cu-TETA-OC and (111)In-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 (64)Cu-TETA-OC was incubated with AR42J cells for 4 h, it was found that the nuclear localization of (64)Cu 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 (64)Cu from [(64)Cu]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 (64)Cu from (64)Cu-TETA-OC is different from that for (64)Cu from [(64)Cu]cupric acetate. The amount of (64)Cu from (64)Cu-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 (64)Cu to the cell nucleus and mitochondria may contribute to cell killing with (64)Cu radiopharmaceuticals.
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Mu
M
Wang
Amy L
AL
Caruano
Michael R
MR
Lewis
Laura A
LA
Meyer
Robert P
RP
VanderWaal
Carolyn J
CJ
Anderson
D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003301:Copper Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015282:Octreotide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D013347:Subcellular Fractions / Q000378:metabolism
D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C421169:copper 1,4,8,11--tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid-octreotide; D004369:Pentetic Acid; D015282:Octreotide