Intracellular putrescine and spermidine deprivation induces increased uptake of the natural polyamines and methylglyoxal bis(guanylhydrazone)

Abstract

Inhibition of polyamine synthesis by .alpha.-difluoromethylornithine in cultured [mouse] Ehrlich ascites carcinoma cells rapidly enhanced the uptake of exogenous putrescine, spermidine and spermine from the culture medium. In tumor cells exposed to the drug for 2 days, the intracellular concentration of spermidine was decreased to less than 10% of that found in untreated cells. The strikingly stimulated transport system brought the concentration of spermidine to the control values in less than 2 h after supplementation of the cells with micromolar concentrations of the polyamine. In the absence of polyamine deprivation, tumor cells did not accumulate extracellular polyamines to any appreciable extent. Ascites tumor cells deprived of putrescine and spermidine likewise concentrated methylglyoxal bis(guanylhydrazone) {1,1''-[(methylethanediylidene)dinitrilo]diguanidine} at a greatly enhanced rate. A previous priming of tumor cells with difluoromethylornithine followed by an exposure of the cells to methylglyoxal bis(guanylhydrazone) resulted in a marked and rapid anti-proliferative effect.