Inhibition of biosynthetic processes in P388 and Ehrlich ascites cells by cloturin.

The effect of cloturin on biosynthesis of DNA, RNA and proteins in both P388 and Ehrlich ascites carcinoma (EAC) cells have been studied in vitro. Biosynthesis of macromolecules indicated by the incorporation rate of [14C]adenine (DNA, RNA), [14C]thymidine (DNA), [14C]uridine (RNA) and [14C]valine (proteins) were studied for concentration (75 to 600 mumol/l) and time dependence. Cloturin inhibits incorporation of all 14C-precursors into the TCA-insoluble fraction of both types of cells in proportion to its concentration. The complete inhibition of 14C-precursors was reached at the highest concentrations of cloturin (300 and 600 mumol/l). The fact that incorporation of four precursors is inhibited suggests that the effect of cloturin lies at an underlying level of energy generation or transfer, rather than at specific reactions in the biosynthesis of DNA and proteins. The rate of DNA synthesis is rapidly affected by the lowering of the level of any of the four deoxyribonucleotide triphosphates. Interference with the generation of high-energy phosphate bonds is one of the mechanisms available for induction of nucleotide deficiency. A depletion of nucleotide pools can serve as an efficient tool to inhibit cellular growth and to induce cell death under some circumstances.