CELLULAR PHARMACOLOGY OF P120 ANTISENSE OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATE ISIS-3466

Previous studies demonstrated that an antisense phosphorothioate oligo deoxynucleotide, ISIS 3466, to the human nucleolar p120 protein, marke dly inhibited the growth of human tumor cell lines in vitro and inhibi ted the growth of the human LOX tumor in vivo in an i.p./i.p. model, i n the presence of DOTMA (Perlaky et al., Anti-Cancer Drug Design 8:3-1 4, 1993). In vitro, DOTMA enhanced the effect of the antisense oligode oxynucleotide more than 100 times. In the presence of DOTMA (10 mu g/m L), 5-15 times more oligodeoxynucleotide was associated with the LOX c ells after 4 hr treatment than in the absence of DOTMA. A 100-fold hig her concentration of the oligodeoxynucleotide was required to introduc e the same amount of oligodeoxynucleotide into the cells in the absenc e of DOTMA than in the presence of DOTMA. Kinetic analysis showed that the cell-associated oligodeoxynucleotide accumulated rapidly and reac hed a plateau after 1 hr incubation. When these cells were placed in a complete medium without the oligodeoxynucleotide, there was a 50% dec rease in the oligodeoxynucleotide after 21 hr. A 35% reduction of p120 mRNA and a 50% reduction of p120 protein was found after ISIS 3466 tr eatment. Further study is needed to explore the tumor-inhibitory mecha nisms of the effects of antisense oligodeoxynucleotide ISIS 3466.