title: Inhibition of nucleic acid synthesis in P-388 lymphocytic leukemia tumor cells by helenalin and bis(helenalinyl)malonate in vivo.
abstract: Although the parent sesquiterpene lactone, helenalin, and its derivative, bis(helenalinyl)malonate, are structurally related chemically, they demonstrate differences in their antineoplastic activity, with bis(helenalinyl)malonate being much more active against P-388 lymphocytic leukemia cell growth (T/C% = 261) compared with helenalin (T/C% = 162). Previous studies have shown that both agents strongly inhibit protein synthesis in vivo by greater than 70% after 3 d of administration and in vitro by 50% at a 100 microM concentration of drug. This inhibition of protein synthesis of P-388 cells may be partially responsible for the cytotoxicity of the drug. These agents also inhibit nucleic acid synthesis in vivo, with DNA synthesis being suppressed by greater than 90% after 2 d of administration of drugs at the therapeutic dose. Of the sulfhydryl-bearing enzymes involved in nucleic acid synthesis that were assayed, only the activities of inosine-5'-monophosphate (IMP) dehydrogenase and the ribonucleotide reductase complex were inhibited by greater than 50% by these sulfhydryl-reactive drugs, which would account for the observed inhibition of nucleic acid synthesis in the P-388 cells. The inhibition of the activities of these enzymes lowered the deoxyribonucleotide levels in P-388 cells, which would explain the overall suppression of DNA synthesis by the sesquiterpene lactones.
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy*; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D012717:Sesquiterpenes / Q000627:therapeutic use*; D045789:Sesquiterpenes, Guaiane; D013729:Terpenes / Q000627:therapeutic use*; D013879:Thioredoxins / Q000037:antagonists & inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D013729:Terpenes; C001329:helenalin; D013879:Thioredoxins; C037387:bis(helenalinyl)malonate; D007168:IMP Dehydrogenase