ENHANCEMENT OF CHEMOSENSITIVITY BY TYRPHOSTIN AG825 IN HIGH-P185(NEU)EXPRESSING NON-SMALL-CELL LUNG-CANCER CELLS

The HER-2/neu gene product, p185(neu), is a membrane-bound receptor wi th tyrosine kinase activity, High levels of p185(neu) is correlated wi th intrinsic chemoresistance of non-small cell lung cancer (NSCLC) cel l lines, We investigated the effects of tyrphostin AG825, a selective tyrosine kinase inhibitor preferentially inhibiting HER-2/neu kinase, on the chemosensitivities and on the drug-induced cell cycle changes o f NSCLC cell lines that expressed different levels of p185(neu), Compa red to the low-p185(neu) expressing cell lines, we found that the high -p185(neu) expressing cell lines were more resistant to doxorubicin, e toposide, and cis-diamminedichloroplatinum(II) but more sensitive to A G825. AG825 was able to significantly enhance the chemosensitivities o f the high-p185(neu) expressing cell lines, whereas it had little effe ct on the chemosensitivities of the low-p185(neu) expressing cells, wi th a few exceptions in which minor antagonistic effects were observed, Although high concentrations of AG825 could reduce the drug-induced G (2) arrest that was accompanied by the activation of phosphorylated p3 4(cdc2), we failed to find any remarkably differential effects of AG82 5 on drug-induced G(2) arrest and the accompanying phosphorylation sta tus of p34(cdc2) of the high- and the low-p185(neu) expressing cell li nes, In summary, tyrphostin AG825 can enhance chemosensitivity in high - but not in low-p185(neu) expressing NSCLC cell lines, This different ial effect cannot be explained by the alterations of drug-induced cell cycle changes by AG825, Our results provide a rationale to develop p1 85(neu)-specific tyrphostin and to test them in combination with antic ancer agents in vivo and in clinical trials.