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At least 19 recordsLinked to original sources
PubMed2004

The anticancer drug ellipticine forms covalent DNA adducts, mediated by human cytochromes P450, through metabolism to 13-hydroxyellipticine and ellipticine N2-oxide.

Ellipticine is an antineoplastic agent, the mode of action of which is considered to be based on DNA intercalation and inhibition of topoisomerase II. We found that ellipticine also forms the cytochrome P450 (CYP)-mediated covalent DNA adducts. We now identified the ellipticine metabolites formed by human CYPs and elucidated the metabolites responsible for DNA binding. The 7-hydroxyellipticine, 9-hydroxyellipticine, 12-hydroxyellipticine, 13-hydroxyellipticine, and ellipticine N(2)-oxide are generated by hepatic microsomes from eight human donors. The role of specific CYPs in the oxidation of ellipticine and the role of the ellipticine metabolites in the formation of DNA adducts were investigated by correlating the levels of metabolites formed in each microsomal sample with CYP activities and with the levels of the ellipticine-derived deoxyguanosine adducts in DNA. On the basis of this analysis, formation of 9-hydroxyellipticine and 7-hydroxyellipticine was attributable to CYP1A1/2, whereas production of 13-hydroxyellipticine and ellipticine N(2)-oxide, the metabolites responsible for formation of two major DNA adducts, was attributable to CYP3A4. Using recombinant human enzymes, oxidation of ellipticine to 9-hydroxyellipticine and 7-hydroxyellipticine by CYP1A1/2 and to 13-hydroxyellipticine and N(2)-oxide by CYP3A4 was corroborated. Homologue modeling and docking of ellipticine to the CYP3A4 active center was used to explain the predominance of ellipticine oxidation by CYP3A4 to 13-hydroxyellipticine and N(2)-oxide.

Antineoplastic Agents, Phytogenic↗
PubMed2003

Rat microsomes activating the anticancer drug ellipticine to species covalently binding to deoxyguanosine in DNA are a suitable model mimicking ellipticine bioactivation in humans.

Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II. Recently, we found that ellipticine also forms covalent DNA adducts and that the formation of the major adduct is dependent on the activation of ellipticine by cytochrome P450 (P450). We examined rat, rabbit, and human hepatic microsomal samples for their ability to activate ellipticine. The extent of activation was determined by binding of 3H-labeled ellipticine to DNA and by analyzing DNA adducts by 32P-postlabeling. We demonstrate that cytochrome P450 of human hepatic microsomes activating ellipticine to species binding to DNA is analogous to that of rats, but not of rabbits. Most of the ellipticine activation in rat and human hepatic microsomes is attributed to P450 enzymes of the same subfamily, P450 3A1/2 and P450 3A4, respectively, while the orthologous enzyme in rabbit hepatic microsomes, P450 3A6, is much less efficient. With purified enzymes, the major role of P450 3A1 and 3A4 in ellipticine-DNA adduct formation was confirmed. We identified deoxyguanosine as the target for P450-mediated ellipticine binding to DNA using polydeoxyribonucleotides and deoxyguanosine 3'-monophosphate. The results strongly suggest that rats are more suitable models than rabbits mimicking the metabolic activation of ellipticine in humans.

Animals↗
PubMed1982

[Syntheses designed to produce 8-amino ellipticine. Synthesis and pharmacological properties of 8-nitro ellipticine].

The synthesis of 8-nitro ellipticine starting from 6-nitro indole is reported. It is the first derivative of ellipticine substituted in position 8 obtained by total synthesis. In contrast to 9-nitro ellipticine the 8-nitro derivative could until now not be reduced to 8-amino ellipticine. To obtain the latter it was intended to arylate an enamine of the 2,5,8-trimethyloctahydroisoquinolone-6 by 1-chloro 2,4-dinitrobenzene, followed by a reductive cyclization and N-demethylating aromatization. Since the yield of the arylation step was low, the isoquinolone was replaced by 2,5-dimethyl cyclohexanone and the synthesis would have to be completed by addition of a pyridine ring. In the case the yield of the aromatisation was 37%, but the carbazole derivative resisted all formylation attempts. 8-Nitro ellipticine was investigated for its DNA affinity, its cytotoxic activity on L 1210 tumors cells and its toxicity in the mouse. The results obtained were compared with those for 9-nitro ellipticine and in regard to cytotoxicity, with those for the 8- and 9-hydroxy ellipticines.

Alkaloids↗
PubMedDate not supplied

Effects of BD-40, an ellipticine analogue (aza-ellipticine) on cell cycle traverse and DNA synthesis in cultures of synchronized mouse fibroblasts.

BD-40 is a pyrido-pyrrolo-isoquinoline analogue of ellipticine, which possesses oncostatic in vivo activity on experimental tumors, and dose-dependent cytostatic and cytotoxic activities on mammalian cells in culture. In order to appreciate the effects of the drug on the replication of DNA, cultures of murine fibroblasts were synchronized by thymidine double block, and BD-40 was added at the time of the block release. The drug did not interfere with the entry of cells in S phase, but a delay in S-phase transit was observed, regardless of the dose employed. In agreement with these data, DNA synthesis started at the same time in control cells and in BD-40 treated cells, but a significant reduction of 3H thymidine incorporation was found in drug-treated cells. This inhibition was not likely to result from a diminution of the specific activity of 3H-dTTP, since nuclei, isolated from cells previously incubated with the drug, also presented a strong diminution of synthetic activity in the presence of the four nucleoside triphosphate precursors (dNTPs). Analysis by alkaline sucrose gradient centrifugation of DNA synthesized in the presence of BD-40 showed that primary fragments, probably corresponding to the duplication of initial replicons, were normally formed but were not further elongated in cells treated with cytotoxic doses, while they were normally processed (although at a slower rate than in control) with a cytostatic drug concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2007

Mammalian peroxidases activate anticancer drug ellipticine to intermediates forming deoxyguanosine adducts in DNA identical to those found in vivo and generated from 12-hydroxyellipticine and 13-hydroxyellipticine.

Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation, inhibition of topoisomerase II and cytochrome P450-mediated formation of covalent DNA adducts. This is the first report on the molecular mechanism of ellipticine oxidation by peroxidases (human myeloperoxidase, human and ovine cyclooxygenases, bovine lactoperoxidase, horseradish peroxidase) to species forming ellipticine-DNA adducts. Using NMR spectroscopy, the structures of 2 ellipticine metabolites were identified; the major product is the ellipticine dimer, in which the 2 ellipticine skeletons are connected via N(6) of the pyrrole ring of one ellipticine molecule and C9 in the second one. The minor metabolite is ellipticine N(2)-oxide. Using (32)P-postlabeling and [(3)H]-labeled ellipticine, we showed that ellipticine binds covalently to DNA after its activation by peroxidases. The DNA adduct pattern induced by ellipticine consisted of a cluster of up to 4 adducts. The 2 adducts are indistinguishable from the 2 major adducts generated between deoxyguanosine in DNA and either 13-hydroxy- or 12-hydroxyellipticine or in rats treated with ellipticine, or if ellipticine was activated with human hepatic and renal microsomes. The results presented here are the first characterization of the peroxidase-mediated oxidative metabolites of ellipticine and we have proposed species, 2 carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium, as reactive species generating 2 major DNA adducts seen in vivo in rats treated with ellipticine. The study forms the basis to further predict the susceptibility of human cancers to ellipticine.

Animals↗
PubMed2006

Molecular mechanisms of antineoplastic action of an anticancer drug ellipticine.

Ellipticine is a potent antineoplastic agent exhibiting the multimodal mechanism of its action. This article reviews the mechanisms of predominant pharmacological and cytotoxic effects of ellipticine and shows the results of our laboratories indicating a novel mechanism of its action. The prevalent mechanisms of ellipticine antitumor, mutagenic and cytotoxic activities were suggested to be intercalation into DNA and inhibition of DNA topoisomerase II activity. We demonstrated a new mode of ellipticine action, formation of covalent DNA adducts mediated by its oxidation with cytochromes P450 (CYP) and peroxidases. The article reports the molecular mechanism of ellipticine oxidation by CYPs and identifies human and rat CYPs responsible for ellipticine metabolic activation and detoxication. It also presents a role of peroxidases (i.e. myeloperoxidase, cyclooxygenases, lactoperoxidase) in ellipticine oxidation leading to ellipticine-DNA adducts. The 9-hydroxy- and 7-hydroxyellipticine metabolites formed by CYPs and the major product of ellipticine oxidation by peroxidases, the dimer, in which the two ellipticine skeletons are connected via N(6) of the pyrrole ring of one ellipticine molecule and C9 in the second one, are the detoxication metabolites. On the contrary, 13-hydroxy- and 12-hydroxyellipticine, produced by ellipticine oxidation with CYPs, the latter one formed also spontaneously from another CYP- and peroxidase-mediated metabolite, ellipticine N(2)-oxide, are metabolites responsible for formation of two ellipticine-derived deoxyguanosine adducts in DNA. The results reviewed here allow us to propose species, two carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium, as reactive species generating two major DNA adducts seen in vivo in rats treated with ellipticine. The study forms the basis to further predict the susceptibility of human cancers to ellipticine.

Animals↗
PubMed2003

DNA adduct formation by the anticancer drug ellipticine in rats determined by 32P postlabeling.

Ellipticine is a potent antineoplastic agent whose mode of action is considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II. Recently, we found that ellipticine also forms covalent DNA adducts in vitro and that the formation of the major adduct is dependent on the activation of ellipticine by cytochrome P450 (CYP). Here, we investigated the capacity of ellipticine to form DNA adducts in vivo. Male Wistar rats were treated with ellipticine, and DNA from various organs was analyzed by (32)P postlabeling. Ellipticine-specific DNA adduct patterns, similar to those found in vitro, were detected in most test organs. Only DNA of testes was free of the ellipticine-DNA adducts. The highest level of DNA adducts was found in liver (19.7 adducts per 10(7) nucleotides), followed by spleen, lung, kidney, heart and brain. One major and one minor ellipticine-DNA adducts were found in DNA of all these organs of rats exposed to ellipticine. Besides these, 2 or 3 additional adducts were detected in DNA of liver, kidney, lung and heart. The predominant adduct formed in rat tissues in vivo was identical to the deoxyguanosine adduct generated in DNA by ellipticine in vitro as shown by cochromatography in 2 independent systems. Correlation studies showed that the formation of this major DNA adduct in vivo is mediated by CYP3A1- and CYP1A-dependent reactions. The results presented here are the first report showing the formation of CYP-mediated covalent DNA adducts by ellipticine in vivo and confirm the formation of covalent DNA adducts as a new mode of ellipticine action.

Animals↗
PubMed1986

The in vitro involvement of topoisomerase II in the activity of aza-ellipticine analogues is not correlated with drug activity on isolated nuclei.

Aza-ellipticines are DNA intercalative ellipticine analogues with antitumor activity that induce protein-linked DNA breaks in NIH 3T3 cells in culture. The effects of two aza-ellipticine congeners (BD-40 and BR-76) on the activity of purified Calf Thymus type II topoisomerase were studied using pUC13 DNA as substrate. DNA cleavage was stimulated by both molecules at those doses required for inducing lethal effects in cells (DE5O). This effect was reversed by high salt treatment, indicating that it was actually mediated by Topo II. Mapping of cleavage sites on linearized and 3' end-labelled pUC13 DNA showed that ellipticine and aza-ellipticines stimulated the same sites, which differed from those stimulated by m-AMSA. Decatenating activity of Topo II on Trypanosoma cruzi kDNA was both inhibited by ellipticine and BD-40 at concentrations much higher than DE50 concentrations. Activity of aza-ellipticines was also investigated on isolated nuclei. Unlike ellipticine which promoted DNA-breaking activity, BD-40 and BR-76 were repeatedly inactive. Prior treatment of DNA by Proteinase K did not reveal hidden breaks which are formed in intact cells treated with BD-40 (Vilarem et al., 1984, Nucleic Ac. Res. 12, 8653). Concordant with these data, BD-40 did not impair DNA-synthetic activity in isolated nuclei, while Ellipticine largely decreased it. These results indicate that lesions induced in DNA by Aza-ellipticines are mediated by Topo II. The absence of effect of these drugs on isolated nuclei compared to that of Ellipticine may be due to some specific features of the association between Topo II and Aza-ellipticines or reflect a bioactivation step as a prerequisite for in vivo activity.

Alkaloids↗
PubMed2006

Cytochromes P450 reconstituted with NADPH: P450 reductase mimic the activating and detoxicating metabolism of the anticancer drug ellipticine in microsomes.

OBJECTIVES: Ellipticine is a potent antineoplastic agent exhibiting multiple action mechanisms. Recently, we found that after cytochrome P450 (CYP)-mediated oxidation ellipticine forms covalent DNA adducts. Ellipticine oxidation by isolated CYP and its binding to DNA is the target of this study. METHODS: High performance liquid chromatography (HPLC) was employed for separation and characterization of ellipticine metabolites generated by CYPs. The (32)P-postlabeling technique was utilized to determine ellipticine-DNA adducts. RESULTS: Purified CYP enzymes reconstituted with NADPH:CYP reductase oxidized ellipticine to up to five metabolites, 7-hydroxy-, 9-hydroxy-, 12-hydroxy-, 13-hydroxyellipticine and ellipticine N(2)-oxide. However, only CYP1A1 was capable to form all metabolites. Using the reconstituted enzymatic system, we demonstrated that the detoxication ellipticine metabolites, 7-hydroxyellipticine and 9-hydroxyellipticine, are mainly generated by CYP1A1 and 1A2, while those responsible for DNA binding, 13-hydroxy-, 12-hydroxyellipticine and ellipticine N(2)-oxide, by CYP3A1 and 2C3. Likewise, the most efficient CYPs forming DNA adducts from ellipticine were CYP3A1 and 2C3. CONCLUSIONS: The results showed that the system of purified CYPs reconstituted with NADPH: CYP reductase proved for ellipticine oxidation provide a true reflection of the situation in the microsomal membrane.

Animals↗
PubMed1987

In vivo exposure to four ellipticine derivatives with topoisomerase inhibitory activity results in chromosome clumping and sister chromatid exchange in murine bone marrow cells.

A single dose of 9-hydroxy-ellipticine, 2-N-methyl-9-hydroxy-ellipticine, 9-fluoro-ellipticine, and 9-amino-ellipticine (5 to 10 mg/kg body wt, ip) resulted in murine bone marrow toxicity as shown by chromosome clumping, chromatid aberrations, and micronuclei formation. An increase in sister chromatid exchanges (SCE) was also observed. These effects are most likely directly related to the topoisomerase inhibitory effect of these drugs since topoisomerase II is involved in the separation of intertwined chromosomal DNA molecules during mitosis as well as being a mediator of DNA exchanges. The two antitumor drugs 2-N-methyl-9-hydroxy-ellipticine and 9-hydroxy-ellipticine were most genotoxic with chromosome abnormalities occurring in 33-95% of the cells and SCE on the order of 12.3 to 19.2 events per cell. Both of these drugs show high topoisomerase II inhibitory activity in vitro. In contrast, 9-amino-ellipticine and 9-fluoro-ellipticine were less genotoxic with chromosomal abnormalities occurring in 14-17% of the cells and SCE on the order of 7.1 to 7.7 events per cell. These two derivatives are both inactive toward experimental tumors and show less topoisomerase II inhibitory activity in vitro. Our results suggest that the ellipticine drugs owe at least some of their cytotoxicity to their genotoxic effects, which seem to be mediated through interaction with topoisomerase II.

Alkaloids↗
PubMed2002

Covalent binding of the anticancer drug ellipticine to DNA in V79 cells transfected with human cytochrome P450 enzymes.

Ellipticine is a potent antineoplastic agent whose mechanism of action is considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II. Recently, we found that ellipticine also forms covalent DNA adducts and that the formation of the major adduct is dependent on the activation of ellipticine by cytochrome P450 (CYP). We examined a panel of genetically engineered V79 cell lines including the parental line V79MZ and recombinant cells expressing the human CYP enzymes CYP1A1, CYP1A2 or CYP3A4 for their ability to activate ellipticine. The extent of activation was determined by analysing DNA adducts by 32P-postlabelling. Ellipticine was found to be toxic to all V79 cell lines with IC(50) values ranging from 0.25 to 0.40 microM. The nuclease P1 version of the 32P-postlabelling assay yielded a similar pattern of ellipticine-DNA adducts with two major adducts in all cells, the formation of only one of which was dependent on CYP activity. This pattern is identical to that detected in DNA reacted with ellipticine and the reconstituted CYP enzyme system in vitro as confirmed by HPLC of the isolated adducts. Total adduct levels ranged from 2 to 337 adducts per 10(8) nucleotides, in the parental line and in V79 expressing CYP3A4, respectively. As in vitro, human CYP1A2 and CYP1A1 were less active. The results presented here are the first report showing the formation of CYP-mediated covalent DNA adducts by ellipticine in cells in culture, and confirm the formation of covalent DNA adducts as a new mechanism of ellipticine action.

Animals↗
PubMed2006

Solvent effect on the photophysical properties of the anticancer agent ellipticine.

This paper investigates how solution conditions, especially solvent polarity and hydrogen bonding, affect the fluorescence of ellipticine, a natural plant alkaloid with anticancer activity. A total of 16 solvents that cover a wide range of polarities were tested. The ultraviolet (UV) absorption and fluorescence emission of ellipticine were found to be solvent dependent. The absorption and emission maximum shifted to higher wavelengths (red shift) with increased solvent polarity. The difference in absorption and emission maximum (Stokes' shift) was large, approximately 10,000-11,000 cm-1, in polar solvents (with orientation polarizability Deltaf>0.2) but unusually small, approximately 8900 cm-1, in nonpolar solvents (hexane and cyclohexane). Large Stokes' shifts were due to an intramolecular charge transfer (ICT), which was enabled by large solvent polarity and hydrogen bonding of ellipticine with the solvents. Two transitions were found in the Lippert-Mataga plot between (1) nonpolar and semipolar solvents and between (2) semipolar and polar solvents. The first transition reflected the formation of hydrogen bonds between ellipticine and the solvents whereas the second transition indicated that ellipticine underwent an ICT. In addition, the larger extinction coefficients and the longer lifetime of ellipticine obtained in protic solvents were attributed to the formation of stronger hydrogen bonds. The photophysical response of ellipticine to changes in solvent polarity and hydrogen bond formation could be used to infer the location of ellipticine in a heterogeneous medium, namely liposomes in aqueous solution. A relatively large red shift of emission in liposomes indicated that ellipticine may be in a more polar environment with respect to the lipid bilayer, possibly close to the hydrophilic interface.

Antineoplastic Agents↗
PubMedDate not supplied

Comparative physiological disposition of ellipticine in several animal species after intravenous administration.

The physiological dispositon of ellipticine (NSC 71795) has been studied in the mouse, rat, dog and monkey after administration of [1-14C]ellipticine at 6 mg/kg iv (3 mg/kg to monkey). Ellipticine was very rapidly distributed from the blood of all species and was deposited in tissues. The rate of elimination of ellipticine from blood was species-dependent, half-times ranging from 22 min in mouse to 210 min in rat, and probably reflected the rate of metabolism of the drug. The rate of elimination of metabolites from blood was also species-dependent, half-times ranging from 140 min in mouse to 380 min in rat, and probably reflected the rate of biliary secretion of the metabolites. Ellipticine was widely but not uniformly distributed throughout the tissues including brain, and some of the highest concentrations of drug and metabolites were in liver, which is probably the primary site of metabolism. The concentrations of ellipticine and metabolites in tissues were species-dependent, correlating with species differences in rates of metabolism and excretion. All species excreted 80% of the dose via the fecal route and 10% via the urinary route, primarily as metabolites during the first 24 hr after dosing. Metabolites entered the gastrointestinal tract by biliary secretion and ellipticine entered by an ion-trapping mechanism. Evidence is presented that the major pathway for ellipticine metabolism in rat was to 9-hydroxyellipticine, which did not accumulate in liver but was conjugated to its glucuronide and sulfate, which were secreted in bile. Other pathways involved hydroxylation and glucuronide conjugation. The pharmacokinetics of ellipticine are correlated with its toxic side effects, such as acute hypotention and neurological symptoms. They are also correlated with its potential as an antitumor agent, such as its ability to achieve values for the area under the curve of concentration vs. time (CXt) in tumors, which would be adequate for therapy. Based upon these correlations, the drug should be administered in the clinic by iv infusion, or, provided its bioavailability is found to be satisfactory, by the oral route.

Alkaloids↗
PubMed1978

Dissolution and absorption of the antineoplastic agent ellipticine.

Ellipticine, a poorly water-soluble alkaloid, is active in several experimental tumor systems. Marked solubility increases were produced by polyvinylpyrrolidone of varying molecular weights (10,000--160,000) and were optimal (approximately 13 mg/ml at 25 degrees) with polyvinylpyrrolidone mol. wt 10,000. Dissolution of ellipticine--polyvinylpyrrlidone (1:22 w/w) tablets in simulated gastric juice was superior to that of ellipticine hydrochloride polymers without affecting maximum dissolution at 37 degrees. Physiological disposition of ellipticine--polyvinylpyrrolidone was compared with that of the hydrochloride salt and ellipticine in suspension following oral administration at 250 mg/kg in fasted mice. In comparison to the suspension, ellipticine tissue levels were about threefold higher with polyvinylpyrrolidone or hydrochloride preparations. Antitumor activity of the three preparations was evaluated intraperitonneally and orally versus L-1210 leukemia. The optimal dose of ellipticine--polyvinylpyrrolidone and ellipticine hydrochloride was lower than that of the suspension and suggested improved absorption.

Administration, Oral↗