CORRELATION BETWEEN THE INHIBITION OF CELL-GROWTH BY BIS(ETHYL)POLYAMINE ANALOGS AND THE DECREASE IN THE FUNCTION OF MITOCHONDRIA

The antiproliferating effect of nine kinds of bis(ethyl)polyamine anal ogues [three kinds each of bis(ethyl)triamine, bis(ethyl)tetraamine an d bis(ethyl)pentaamine] was compared using FM3 A cells. The inhibitory effect was in the order BE4444 > BE3443 > BE4334 greater than or equa l to BE444 > BE343 > BE333 > BE44 > BE34 > BE33. Our results indicate that not only polyamine deficiency but also the accumulation of polyam ine analogues is involved in the inhibition of cell growth. Accumulati on of bis(ethyl)polyamine analogues caused the inhibition of protein s ynthesis and the decrease in the ATP content. The protein synthetic sy stem in mitochondria was more strongly inhibited by bis(ethyl)polyamin e analogues than that in the cytoplasm. Under conditions such that cyt oplasmic protein synthesis was inhibited by 50% by bis(ethyl)polyamine analogues, mitochondrial protein synthesis was almost completely inhi bited. Mitochondrial Ile-tRNA formation was inhibited by bis(ethyl)pol yamine analogues at the concentrations that cytoplasmic Ile-tRNA forma tion was stimulated. This may be one of the reasons for the selective inhibition of mitochondrial protein synthesis. This inhibition was fol lowed by the decrease in ATP content, swelling of mitochondria and dep letion of mitochondrial DNA. These results suggest that the early even t of metabolic change caused by bis(ethyl)polyamine analogues in cells is the inhibition of protein synthesis, especially of mitochondrial p rotein synthesis.