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Daphnane diterpene esters have previously been shown to have antineoplastic activity in vivo against the growth of P-388 lymphocytic leukemia cells. These studies demonstrate cytotoxic activity of genkwadaphnin and gnidilatidin against P-388 lymphocytic leukemia, L-1210 lymphoid leukemia and human KB carcinoma cell growth in vitro. At the ed50 values in the respective tumor lines DNA synthesis was preferentially suppressed in all three cell lines. RNA synthesis was essentially unaffected by the agents. Protein synthesis inhibition by the two agents demonstrated selectively, e.g. in P-388 cells significant inhibition, in L-1210 cells marginal inhibition and in KB cells no inhibition was observed at these concentrations. Multiple sites in DNA synthesis were found to be inhibited by the daphnane diterpene esters. Two to three times the ed50 concentration in the respective tumor lines was required to observe suppression of DNA synthesis. Purine de novo synthesis appeared to be the major site of inhibition, with inosine monophosphate dehydrogenase and phoshoribosyl pyrophosphate amido transferase activities being inhibited in all three tissue lines. Dihydrofolate reductase activity was inhibited, significant only in the P-388 and KB cells. The magnitude of the enzyme suppression by the agents varied with the tumor line. However, the degree of enzyme suppression was of sufficient magnitude to account for the observed purine and DNA synthesis inhibition by the daphnane diterpene esters.
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