Biochemical studies on growth‐inhibitory bisdioxopiperazines. I. Effect on dna, rna and protein synthesis in mouse‐embryo fibroblasts

Abstract

Abstract A number of bisdioxopiperazines have recently been shown to possess marked growth‐inhibitory activity against a range of experimental tumours in mice and rats. These compounds were originally designed as potential intracellularly activated chelating agents. In the present investigation, two of these compounds (±)‐1,2‐bis (3,5‐dioxopiperazin‐1‐yl) propane (ICRF 159) and meso ‐2,3‐bis (3,5‐dioxopiperazin‐1‐yl) butane (ICRF 193) have been shown to be potent inhibitors of DNA synthesis in growing mouse‐embryo fibroblasts while having relatively little effect on RNA and protein synthesis. In this respect, their behaviour strongly resembles that of radiomimetic drugs and ionizing radiation. X‐rays and both ICRF 159 and ICRF 193 exhibit a very similar pattern for the time‐course of the inhibition of 3 H‐thymidine uptake into DNA. They all show a recovery taking place about 4 h after the initial treatment (presumably due to repair and/or stimulation of unscheduled DNA synthesis) followed later by a more substantial and permanent inhibition. In view of the structure of these compounds, it is possible that they may be exerting a radiomimetic effect by acting as mono‐ or bi‐functional acylating agents.