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Antitumor agents LV: Effects of genkwadaphnin and yuanhuacine on nucleic acid synthesis of P-388 lymphocytic leukemia cells.

The diterpene esters, genkwadaphnin and yuanhuacine, have been shown to possess significant antileukemic activity in the P-388 screen. The major metabolic effects of the diterpene esters were on DNA and protein synthesis. The effects on DNA synthesis in vitro were evoked at a lower concentration than that required for protein synthesis inhibition. The sites in DNA synthesis which were inhibited were DNA polymerase and purine synthesis. In the latter pathway the enzyme activities inhibited were phosphoribosyl aminotransferase, inosinic acid dehydrogenase, and dihydrofolate reductase. In vivo administration of the diterpene esters at 0.8 mg/kg afforded identical types of effects on purine and DNA synthesis and in addition suppressed histone phosphorylation and reduced the number of surviving tumor cells. The in vivo effects on purine and DNA synthesis were evident as early as 6 and 24 hr after administration of a single dose of the diterpene esters.