ANTISENSE OLIGONUCLEOTIDES TO P53 TUMOR-SUPPRESSOR SUPPRESS THE INDUCTION OF APOPTOSIS BY EPIDERMAL GROWTH-FACTOR IN NCI-H-596 HUMAN LUNG-CANCER CELLS

Apoptosis has become a basic tool in developing cancer research and es tablishing new cancer strategies. However, the molecular mechanism of apoptosis is not well understood. Recently, the authors found that epi dermal growth factor (EGF) induces apoptosis in various cancer cells a nd that there is a novel signal pathway mediated through p53 in signal transduction of EGF, The effect of antisense gene therapy to p53 tumo r suppressor on EGF-dependent apoptosis was investigated in cultured N CI-H 596 human non-small cell lung cancer cells with a wild-type p53 g ene, Results showed that EGF plus p53 sense oligonucleotides induced E GF-dependent and p53-dependent apoptosis in NCI-H 596 cells within 8 h ours, On the other hand, antisense gene therapy using antisense oligon ucleotides to p53 tumor suppressor suppressed the induction of EGF-dep endent and p53-dependent apoptosis. Mutated p53 antisense-containing m utated CG dinucleotides had the same effect as that of p53 antisense o n suppression of apoptosis in NCI-H 596 cells. We found that a new nuc leic acid drug, another mutated p53 antisense-containing mutation at t hree bases immediately 5' and 3' from the CG dinucleotides, potentiate d the induction of apoptosis and failed to suppress the induction of E GF-dependent apoptosis. These results suggest that gene therapy using antisense oligonucleotides to the p53 tumor suppressor is effective on EGF-dependent apoptosis of NCI-H 596 human non-small cell lung cancer .