Sequiterpene lactones. Part XXV. Studies on the mode of action. The cellular and molecular basis of cytostatic action.

Two compounds, derivatives of the sesquiterpene lactones (SL), ALA and URSA, on the basis of the high antitumor activity in vitro and in vivo systems, were selected as models, in order to study the mechanism of action of this drug class. Using cytologic, morphologic and isotopic methods the following were demonstrated: 1) At a subtoxic conc., 0.28 microM, arrest the HeLa cell in its interphase (G1, and/or S, G2). 2) At a higher conc. of 28.0 microM, complete and irreversible cytotoxic effects with pyknosis and karyorrhexis. 3) At a conc. of 56.0 microM, inhibition of protein biosynthesis by 94% and RNA by 81--92%. 4) At a conc. of 2.5 microM inhibition by 80% of translation processes. Inhibition of DNA biosynthesis seems to be doubtful. A preliminary hypothetical model of the cellular and molecular mechanism of SL, partly explanatory also of the cytostatic effect, has been proposed.