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.
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Authors | W L Williams Jr, I H Hall, A A Grippo, C B Oswald, K H Lee, D J Holbrook, S G Chaney |
Journal | Journal of pharmaceutical sciences
(J Pharm Sci)
Vol. 77
Issue 2
Pg. 178-84
(Feb 1988)
ISSN: 0022-3549 [Print] United States |
PMID | 2896234
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antineoplastic Agents, Phytogenic
- DNA, Neoplasm
- Neoplasm Proteins
- RNA, Neoplasm
- Sesquiterpenes
- Sesquiterpenes, Guaiane
- Terpenes
- helenalin
- Thioredoxins
- bis(helenalinyl)malonate
- IMP Dehydrogenase
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Topics |
- Animals
- Antineoplastic Agents, Phytogenic
(therapeutic use)
- DNA, Neoplasm
(biosynthesis)
- IMP Dehydrogenase
(antagonists & inhibitors)
- In Vitro Techniques
- Leukemia P388
(drug therapy, metabolism)
- Leukemia, Experimental
(drug therapy)
- Male
- Mice
- Neoplasm Proteins
(biosynthesis)
- RNA, Neoplasm
(biosynthesis)
- Sesquiterpenes
(therapeutic use)
- Sesquiterpenes, Guaiane
- Terpenes
(therapeutic use)
- Thioredoxins
(antagonists & inhibitors)
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