Cellular pharmacology of p120 antisense oligodeoxynucleotide phosphorothioate ISIS 3466.
Previous studies demonstrated that an antisense phosphorothioate oligodeoxynucleotide, ISIS 3466, to the human nucleolar p120 protein, markedly inhibited the growth of human tumor cell lines in vitro and inhibited the growth of the human LOX tumor in vivo in an i.p./i.p. model, in the presence of DOTMA (Perlaky et al., Anti-Cancer Drug Design 8:3-14, 1993). In vitro, DOTMA enhanced the effect of the antisense oligodeoxynucleotide was associated with the LOX cells after 4 hr treatment than in the absence of DOTMA. A 100-fold higher concentration of the oligodeoxynucleotide was required to introduce the same amount of oligodeoxynucleotide into the cells in the absence of DOTMA than in the presence of DOTMA. Kinetic analysis showed that the cell-associated oligodeoxynucleotide accumulated rapidly and reached a plateau after 1 hr incubation. When these cells were placed in a complete medium without the oligodeoxynucleotide, there was a 50% decrease in the oligodeoxynucleotide after 21 hr. A 35% reduction of p120 mRNA and a 50% reduction of p120 protein was found after ISIS 3466 treatment. Further study is needed to explore the tumor-inhibitory mechanisms of the effects of antisense oligodeoxynucleotide ISIS 3466.
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030.
Y
Y
Saijo
L
L
Perlaky
B C
BC
Valdez
H
H
Wang
D
D
Henning
H
H
Busch
D001483:Base Sequence; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D018328:Melanoma, Amelanotic / Q000188:drug therapy; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D013873:Thionucleotides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004273:DNA, Neoplasm; D006131:Growth Inhibitors; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense; D000644:Quaternary Ammonium Compounds; D012334:RNA, Neoplasm; D013873:Thionucleotides; C054005:N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium; C085418:ISIS 3466