CONTIGUOUS 4-GUANOSINE SEQUENCE IN C-MYC ANTISENSE PHOSPHOROTHIOATE OLIGONUCLEOTIDES INHIBITS CELL-GROWTH ON HUMAN LUNG-CANCER CELLS - POSSIBLE INVOLVEMENT OF CELL-ADHESION INHIBITION

A contiguous four-guanosine (4G) sequence in c-myc antisense phosphoro thioate oligonucleotides caused an antiproliferative effect in smooth muscle cells. To investigate the antiproliferative effect of c-myc ant isense oligonucleotides on human lung cancer cell lines, we synthesize d oligonucleotides of various lengths and sequences, focusing on the c ontiguous four-guanosine (4G) sequence. While a c-myc antisense oligon ucleotide (20AS1 (4G)) targeted to the translation initiation codon of c-myc mRNA inhibited cell growth of A549 cells by 69% at 10 mu M, a s crambled oligonucleotide (2OSCR1 (4G)) containing the contiguous four- guanosine (4G) sequence also inhibited cell growth by 72% at the same dose. Although treatment with either 20AS1 (4G) or 20SCR1 (4G) inhibit ed cell adhesion by 70% at 10 mu M, expression of c-myc protein was si gnificantly suppressed only by 20AS1 (4G) (62%), and was only weakly i nhibited by 20SCR1 (4G) (32%). Furthermore, a small cell lung carcinom a cell line, Lu65, which can grow in suspension form, was highly resis tant to 20AS1 (4G) treatment (IC50 >20 mu M). These results suggest th at the cell growth inhibition by c-myc antisense oligonucleotides cont aining the contiguous four-guanosine (4G) sequence was possibly correl ated with inhibition of cell adhesion, but not with inhibition of c-my c protein expression, via a sequence-specific non-antisense mechanism.