Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-2-(Diethylaminoethyl)-9-hydroxyellipticinium chloride (DHE) is a structural analogue of ellipticine that is currently a leading compound for clinical trials. We have investigated the mechanism of DNA damage by this compound in murine L1210 leukemia cells using the method of alkaline elution. Although DHE was about 100-fold more cytotoxic than ellipticine, this increased cytotoxicity was not accompanied by greater amounts of DNA strand breakage or protein-DNA cross-linking. The single strand breaks caused by both compounds were protein associated and could be accounted for by the presence of double strand breaks. DNA damage by the compounds therefore was consistent with topoisomerase II inhibition. Unlike DHE, 80% of the DNA damage elicited by ellipticine was repaired within 1 h after removal of drug. For DHE, 20-h incubations in drug-free media were required to obtain 70% repair of single strand DNA breaks. These data indicated that although both ellipticine and DHE may inhibit topoisomerase II, the type of DNA damage which resulted in topoisomerase II inhibition by DHE was much more persistent than the DNA damage elicited by ellipticine.
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PMID:DNA damage and cytotoxicity in L1210 cells by ellipticine and a structural analogue, N-2-(diethylaminoethyl)-9-hydroxyellipticinium chloride. 154 Sep 60

2-(Diethylamino-2-ethyl)9-hydroxyellipticinium-chloride, HCl (DHE), a new congener of the antitumor agent elliptinium acetate (Celiptium) (NMHE), has recently been selected for phase I clinical trials. NMHE has a methyl group at nitrogen 2 on the ellipticine ring while DHE possesses a basic diethylaminoethyl chain at this position. Compared to NMHE, the presence of the diethylaminoethyl side chain results in the following: a significant increase in the lipophilicity of the drug; no significant modification in either the binding constant values to DNA or the ability to intercalate between DNA base pairs; a marked decrease in the unwinding angle value of supercoiled DNA; and no significant change in the alteration of the catalytic activity of topoisomerase II in vitro. DHE appears to act as a simple reversible intercalating agent as shown by the selective mutagenic effect on Salmonella TA 1977 tester strain and by its inability to induce the SOS functions in a sfiA lac fusion containing Escherichia coli strain. From a pharmacological point of view, the presence of the diethylaminoethyl chain results in a 2-fold increase in the cytotoxicity to L1210 cultured cells, a strong increase in the antitumor efficiency on experimental murine tumors such as L1210 and P388 leukemia, B16 melanoma, M 5076 reticulosarcoma, and colon 38 adenocarcinoma, and finally an objective decrease in the acute and subacute toxicity in mice, rat, and macaque. The absence of significant differences in the interaction of NMHE and DHE with their potential targets in vitro leads to the hypothesis that the superiority of DHE in terms of cytotoxicity and antitumor efficiency may be due to an increase in the diffusion across cellular membrane and a more favorable biodistribution in vivo.
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PMID:Physicochemical and pharmacological properties of the antitumor ellipticine derivative 2-(diethylamino-2-ethyl)9-hydroxy ellipticinium-chloride, HCl. 367 74