Molecular therapy of human neuroblastoma cells using Auger electrons of 111In-labeled N-myc antisense oligonucleotides.
Auger electrons can create breaks in nucleic acids, giving them possible therapeutic utility. We investigated the therapeutic effect of Auger electrons emitted by 111In-labeled phosphorothioate antisense oligonucleotides on human neuroblastoma cells in which N-myc was overexpressed.


METHODS
Human SK-N-DZ neuroblastoma cells (5 x 10(6) cells) were treated with cationic reverse-phase evaporation vesicles (REVs) encapsulating 111In-labeled antisense (40 MBq/2 nmol of oligonucleotides/mumol of total phospholipids) that had an average diameter of 250 nm. Hybridization of the radiolabeled oligonucleotides with N-myc messenger RNA (mRNA), N-myc expression, and cell proliferation were investigated. The tumorigenicity of treated cells was analyzed in nude mice. Nonradiolabeled antisense, 111In-labeled sense, or empty cationic REVs were used as controls.


RESULTS
111In-Labeled antisense, which hybridized with N-myc mRNA, was detected in cells at 12 and 24 h after the initiation of treatment. Reduced N-myc expression and inhibited cell proliferation were shown in the same cells at 48 h after the completion of treatment. N-myc expression-suppressed cells produced intraperitoneal tumors in nude mice, but the average weight of the tumors was lower than that of tumors in control mice.


CONCLUSIONS
Auger electrons emitted from 111In in close proximity to their target N-myc mRNA may prolong the time to cell proliferation in human neuroblastoma cells due to inhibition of the translation of N-myc. Auger electron therapy therefore has potential as an internally delivered molecular radiotherapy targeting the mRNA of a tumor cell.
Watanabe
Naoyuki
N
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan. N.Watanabe@iaea.org
Sawai
Hiroaki
H
Ogihara-Umeda
Izumi
I
Tanada
Shuji
S
Kim
E Edmund
EE
Yonekura
Yoshiharu
Y
Sasaki
Yasuhito
Y
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004583:Electrons; D005260:Female; D016259:Genes, myc; D006801:Humans; D007205:Indium Radioisotopes / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000473:pathology / Q000532:radiotherapy*; D009693:Nucleic Acid Hybridization; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D012333:RNA, Messenger / Q000737:chemistry; D014183:Transplantation, Heterologous
D007205:Indium Radioisotopes; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger