Depression Of Polyamine Synthesis In L1210 Leukemic Mice During Treatment With A Potent Antileukemic Agent, 5-Azacytidine

Summary Polyamine metabolism was studied in spleens and livers of BDF1 mice after i.p. inoculations of 106 L1210 leukemic cells. The spleen is rapidly invaded by the tumor cells and may accurately reflect the tumor activity throughout its time course. All the enzymes in the polyamine-biosynthetic pathway, ornithine decarboxylase, and putrescine-dependent and spermidine-dependent S-adenosyl-l-methionine decarboxylases were markedly elevated in the spleens of the leukemic mice. Concomitantly, the concentrations of putrescine and spermidine increased, while that of spermine remained unchanged. Dramatic changes were also seen in the endogenous concentrations of polyamines in the liver. When 5-azacytidine, one of the most effective antileukemic agents thus far tested, was injected i.p. on Days 1 through 9 (3.0 μg/g of body weight) into mice inoculated on Day 0 with L1210 ascites tumor cells, the mean survival time was 300% that of untreated leukemic mice. During drug treatment all enzymes in the polyamine-biosynthetic pathway were markedly depressed and, further, the accumulations of polyamines normally observed in leukemic mice were inhibited. The weight of the spleens, which more than doubled in leukemic mice by Day 7, declined to near normal in the drug-treated leukemic mice. When 5-azacytidine injections were stopped, there was a rapid increase in both the synthesis and accumulation of polyamines in the spleen, accompanied by an increase in the spleen weight. Host toxicity was not evident in mice that received the 9-day 5-azacytidine regimen.