ENHANCEMENT OF ANTIPROLIFERATIVE ACTIVITIES OF 5-FU, HCFU, SN-38, THPAND ACNU BY A SERINE-PROTEASE INHIBITOR, FOY-305

The effects of a synthetic serine protease inhibitor, FOY-305, on the proliferation of normal and transformed mouse fibroblasts were investi gated in vitro by MTT colorimetric assay. FOY-305 inhibited the growth of normal NIH3T3 cells and their src- and erbB2-transformed cells wit h a half maximum inhibitory concentration (IC50) of 1-1.2 mg/ml wherea s it suppressed the growth of ras-transformed cells more effectively ( IC50 was 0.5-0.6 mg/ml). Flow cytometric analysis using synchronized N IH3T3 cells has shown that the growth-inhibitory activity of FOY-305 w as due to the suppression of G(1)/S transition. The synergistic effect s between FOY-305 and traditional anticancer drugs were also investiga ted by the MTT assay and the results showed that FOY-305 significantly enhanced the antiproliferative activities of 5-fluorouracil (5-FU), 1 -hexylcarbamoyl-5-fluorouracil (HCFU), hydroxy-7-ethyl-10-[4-(1-piperi dino)-1-piperidino] camptothecin (SN-38), pirarubicin (THP) and -pyrim idinyl)-methyl-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU).