Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of three acridine derivatives, 9-aminoacridine (9AA), 4'-(9-acridinylamino)-methanesulphon-O-anisidide (O-AMSA) and quinacrine were compared in their ability to protect against the cytotoxicity of amsacrine, 9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridine-carboxamide (CI-921), N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC), etoposide, mitoxantrone and doxorubicin. Cytotoxicity was measured in vitro by clonogenic survival assay and in vivo by life extension assays. All three acridine derivatives protected a Lewis lung cell line in vitro against CI-921, with 9AA having the highest activity. Cellular uptake of [14C] CI-921 by cultured Lewis lung cells was unaffected by 9AA, and slightly stimulated by O-AMSA and quinacrine. 9AA protected Lewis lung cells in vitro against the cytotoxicity of amsacrine, CI-921, AC and etoposide, partially against mitoxantrone but not against doxorubicin. A similar result was obtained with the human melanoma cell line MM96, where 9AA protected against CI-921 but not against doxorubicin toxicity. 9AA protected P388 leukaemia in vivo against amsacrine, CI-921 and AC cytotoxicity, partially against etoposide but not against mitoxantrone or doxorubicin. 9AA also protected against animal toxicity caused by high dose amsacrine and partially against CI-921 toxicity. It is hypothesized that DNA intercalating chemoprotectors act by restricting the conformational flexibility of the DNA and thus the ability of topoisomerase II to form a 'cleavable complex' in which the DNA is covalently linked to the enzyme.
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PMID:Chemoprotection by 9-aminoacridine derivatives against the cytotoxicity of topoisomerase II-directed drugs. 256 Oct 99

We have compared the effects of a number of inhibitors including aphidicolin, 2,4-dinitrophenol (DNP) and novobiocin on the in vitro cytotoxicity of several topoisomerase II (topo II)-directed agents, using cultured murine Lewis lung carcinoma cells. These agents comprised amsacrine, CI-921 (9-[(2-methoxy-4-methylsulfonylamino)phenylamino]-N,5-dimethyl-4- acridinecarboxamide isethionate, isethionate, a derivative of amsacrine), DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride, a new DNA intercalator with high solid tumor activity), daunorubicin, doxorubicin, epirubicin, etoposide, mitoxantrone, and teniposide. Novobiocin, an antibiotic that affects topo II action, reduced the cytotoxic effect of DACA as well as that of amsacrine and doxorubicin, and reduced the extent of G2-phase arrest by DACA. DNP, an uncoupler of mitochondrial respiration, inhibited drug action in a manner similar to that of novobiocin but to a smaller extent. Aphidicolin, a specific inhibitor of DNA polymerase-alpha, reduced the cytotoxic effect of amsacrine, CI-921, etoposide, and teniposide but not that of DACA, daunorubicin, doxorubicin, epirubicin, or mitoxantrone. The immediate effect of each topo II-directed agent on the incorporation of thymidine into DNA was also measured at a drug concentration (D10) that killed 90% of cells. Susceptibility to aphidicolin reversal was strongly correlated with inhibition of thymidine incorporation (r = 0.91; p < or = 0.001). The results suggest that the involvement of DNA replication in the cytotoxic action of topo II-directed agents differs according to the agent used.
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PMID:A comparison of the effects of aphidicolin and other inhibitors on topoisomerase II-directed cytotoxic drugs. 826 Jul 50

1. The solid tumour has various properties which tend to minimize the effects of a cytotoxic agent; the low vascular density of tumours, in particular, limits the diffusion of many anti-tumour drugs. 2. This applies particularly to two general classes of anti-cancer drugs which already play an important role in chemotherapy: mitotic poisons and topoisomerase poisons. Such compounds bind strongly to proteins and/or DNA, and their diffusion from the bloodstream into solid tumours is slow, as is their clearance from tumour tissue. 3. The specific questions posed here is whether anti-cancer compounds of these types are more cytotoxic when administered at a low concentration for a long time (mimicking conditions in solid tumours) than at a correspondingly high concentration for a short time (mimicking conditions in host tissue). Two possible principles may be involved, the first based on cytokinetic considerations and then second on self-inhibition of drug cytotoxicity. 4. Using cultured human cancer cells we have shown that taxol, which acts on mitotic cells and camptothecin, which acts on S-phase cells, are examples of the first principle. Exposures to high drug concentrations for short times are much less cytotoxic than exposure to correspondingly lower drug concentrations for a longer time (with the same concentration x time of exposure). We also show that the drug DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) developed in this laboratory and currently undergoing clinical trial, achieves the same result through the principle of self-inhibition of cytotoxicity. 5. Matching of the cytokinetic or self-inhibitory profile of a drugs' action with the pharmacokinetics of drug in tumours may provide new drugs with increased anti-tumour effects.
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PMID:Pharmacokinetic/cytokinetic principles in the chemotherapy of solid tumours. 859 37

A number of acridine derivatives, including the clinical antileukaemia agent amsacrine and the experimental agent DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide), target the enzyme topoisomerase II. We demonstrate here that DACA induces DNA cleavage in the presence of topoisomerase I as well as of topoisomerase II. We also investigate a series of acridine derivatives which link amsacrine to DACA in terms of DNA binding, topoisomerase poisoning and biological activity. The presence of an acridine 4-linked N-2-(dimethylamino)ethyl group provides both a pronounced G-C preference for DNA binding and activity towards topoisomerase I. The removal of the anilino side chain of amsacrine, in combination with the presence of the N-2-(dimethylamino)ethyl group, provides in vitro biological activity against "atypical" multidrug resistant leukaemia lines with low topoisomerase II activity. Among these compounds, suppression of the ionisation of the acridine nitrogen to produce the compound DACA is associated with experimental activity against solid tumours. The addition of an acridine 2-chloro substituent to DACA suppresses the stimulation of topoisomerase II-dependent DNA cleavage but increases stimulation of topoisomerase I cleavage. 2-Substitution also increases activity against the "atypical" multidrug resistant cell lines. Overall, the results suggest that augmentation of topoisomerase I-dependent activity in this series by appropriate chemical substitution in this series leads to circumvention of topoisomerase II-mediated multidrug resistance.
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PMID:From amsacrine to DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide): selectivity for topoisomerases I and II among acridine derivatives. 869 77

We studied the role of DNA topoisomerase II in the biological actions of a series of novel alkylaminoanthraquinones, including N-oxide derivatives designed as prodrugs liable to bioreductive activation in hypoxic tumour cells. Drug structures were based upon the DNA-binding anticancer topoisomerase II poison mitoxantrone with modifications to the alkylamino side chains. The agents included AQ4, 1,4-bis{[2-(dimethylamino)ethyl] amino}5,8-dihydroxy-anthracene-9,10-dione, and AQ6, 1{[2-dimethylamino)-ethyl]amino}4-{[2[(hydroxyethyl)amino]ethyl]- amino}5,8-dihydroxy-anthracene-9,10-dione, together with the corresponding mono-N-oxide (AQ6NO) and di-N-oxide (AQ4NO). The R3N(+)-O- modification renders the terminal nitrogen group electrically neutral and was found to reduce AQ6NO or effectively abolish AQ4NO-DNA binding. Comparative studies were carried out using two SV40-transformed fibroblast cell lines, MRC5-V1 and AT5BIVA, the latter being a relative overproducer of DNA topoisomerase II alpha. The inhibition of DNA topoisomerase II decatenation activity ranked according to DNA-binding capacity. A similar ranking was found for drug-induced DNA-protein cross-linking in intact cells, depending upon topoisomerase II availability. Inhibition of DNA synthesis in S-phase synchronized cultures ranked in the order of AQ6 > mitoxantrone > > AQ6NO and was independent of topoisomerase II availability. Cytotoxicity of acute 1-h exposures for all agents except the inactive AQ4NO was enhanced in the topoisomerase II-overproducing cell line. The results indicate an important role for enzyme targeting in anthraquinone action. However, DNA synthesis inhibition and cytotoxicity were greater than expected for AQ6, given its topoisomerase- and DNA-interaction properties, and parallel studies have provided evidence of an additional role for enhanced subcellular accumulation and nuclear targeting. The inactivity of AQ4NO and the retention of only partial activity of AQ6NO, allied with the effective topoisomerase II-targeting and high cytotoxic potential of their presumed metabolites, favour their use as prodrugs in tumour cells with enhanced bioreductive potential.
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PMID:DNA topoisomerase II-dependent cytotoxicity of alkylaminoanthraquinones and their N-oxides. 905 61

The mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is currently in clinical trial as an anticancer drug. A series of acridine-substituted analogues were prepared, using a new synthetic route to substituted acridine-4-carboxylic acids (conversion of substituted diphenylamine diacid monoesters to the corresponding aldehydes and mild acid-catalyzed ring closure to form the acridines directly). The analogues were evaluated in a panel of cell lines which included wild-type (JLC) and mutant (JLA and JLD) forms of the human Jurkat leukemia line. The latter mutant lines are resistant to topoisomerase II targeted agents due to lower levels of the enzyme. Structure-activity studies suggest that the electronic properties of the substituents do not markedly affect cytotoxicity, but steric bulk is important, with larger groups leading to loss of activity. The compounds fell broadly into two categories. The majority had cytotoxicities similar to (or lower than) that of DACA itself and were equitoxic in all the Jurkat lines, suggesting a relatively greater effect on topoisomerase I compared with topoisomerase II. Most of the 5-substituted derivatives and the 7-Ph compound were more cytotoxic than DACA, but were less effective against JLA and JLD cell lines than in the wild-type JLC, suggesting a mode of cytotoxicity largely mediated by effects on topoisomerase II. Both DACA and selected acridine-substituted analogues were active in the relatively refractory subcutaneous colon 38 tumor model in vivo.
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PMID:Structure-activity relationships for acridine-substituted analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide. 919 70

An antitumor drug N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and its three close structural analogs N-[2-(hydroxyethylamino)ethyl]acridine-4-carboxamide (DACAH), N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (amino-DACA), and N-[2-(hydroxyethylamino)ethyl]-9-aminoacridine-4-carboxamide (amino-DACAH) were studied for their ability to inhibit RNA synthesis in vitro and to form topoisomerase II-mediated DNA lesions in relation to cell-killing activity. All tested compounds induced chromatin lesions characteristic of topoisomerase II-blocking drugs (DNA breaks and DNA-protein cross-links) in treated cells, but were much less active than reference antileukemic acridine m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide). The ability to form these lesions was dependent on the structure of the 4-carboxamide side-chain, which seems to be an important factor affecting the drug transport rate through cell membrane. A 4-carboxamide chain with an N-2-(dimethylamino)ethyl moiety resulted in more efficient transport through cell membranes, higher cytotoxicity, and DNA-damaging activity. The mode of action of acridine-4-carboxamides was further elucidated by their incubation with cells in the presence of antitopoisomerase II agents of a known mechanism of inhibition. These were: bisdioxopiperazine (ICRF-187), a catalytic inhibitor of topoisomerase II, and etoposide (VP-16), an inducer of a cleavable complex of the enzyme with DNA. The cytotoxicity of DACA and its analogs was not antagonized by preincubating cells with ICRF-187. All tested acridines protected cells against DNA breakage induced by VP-16, but the extent of protection varied significantly. Amino-DACA, which easily penetrates cell membrane, fully inhibited DNA break formation, whereas other analogs exhibited a low degree of protection when used at high concentration. Our results suggest that the acridine-4-carboxamides discussed here are poor topoisomerase II poisons and that this enzyme is not their main target.
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PMID:Cytotoxic and DNA-damaging properties of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and its analogues. 974 73

DACA [N-[2-(dimethylamino)ethyl]acridine-4-carboxamide], an acridine derivative that is highly active against solid tumours in mice, is currently in clinical trial. The ability of DACA to overcome "atypical" (topoisomerase II-mediated) multidrug resistance has been hypothesised to stem from its dual topoisomerase I/II specificity. We investigated the topoisomerase specificity of DACA and its 7-chloro derivative (C1-DACA) using camptothecin and amsacrine as control compounds. In cell-free assays employing supercoiled plasmid DNA, C1-DACA at 5 microM induced topoisomerase I-mediated DNA breakage, indicating cleavable complex formation (poisoning), and at 10 microM it inhibited relaxation of DNA, consistent with suppression (self-inhibition) of poisoning. In this assay, DACA provided no evidence of poisoning of this enzyme but inhibited its function at concentrations above 10 microM. In DNA cleavage assays utilising purified topoisomerase II, DACA induced breakage of supercoiled plasmid DNA at 5 microM whereas C1-DACA showed very weak poisoning at 1 microM and inhibition at 5 microM. Under conditions required for the assay of DNA relaxation, C1-DACA, but not DACA, inhibited topoisomerase II action at 5 microM. The actions of DACA and C1-DACA could also be distinguished by their ability to form DNA-protein cross-links in H460 human lung carcinoma cells as measured by precipitation of DNA-protein complexes with sodium dodecyl sulfate and potassium chloride. Both drugs stimulated the formation of complexes at low concentrations but inhibited formation at high concentrations. In survival assays with H460 cells, both drugs demonstrated biphasic responses with self-inhibition of cytotoxicity at intermediate drug concentrations. It was concluded that although both drugs have dual topoisomerase I/II specificity, DACA preferentially poisons topoisomerase II and C1-DACA preferentially poisons topoisomerase I. In addition, drug-induced inhibition of topoisomerase action at higher drug concentrations may mask poisoning in the cell-free assays as well as masking cytotoxicity in cultured cells. A model in which drug binding occludes topoisomerase-binding sites on the DNA can explain this self-inhibition of cytotoxic action.
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PMID:Mechanism of cytotoxicity of N-[2-(dimethylamino)ethyl] acridine-4-carboxamide and of its 7-chloro derivative: the roles of topoisomerases I and II. 1007 81

A series of acridine-substituted bis(acridine-4-carboxamides) linked by a (CH2)3N(Me)(CH2)3 chain have been prepared by reaction of the isolated imidazolides of the substituted acridine-4-carboxylic acids with N,N-bis(3-aminopropyl)methylamine. These dimeric analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), currently in clinical trial, show superior potencies to the corresponding monomeric DACA analogues in a panel of cell lines, including wild-type (JLC) and mutant (JLA and JLD) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase II targeted agents because of lower levels of the enzyme. Analogues with small substituents (e.g., Me, Cl) at the acridine 5-position were clearly superior, with IC50's as low as 2 nM against the Lewis lung carcinoma and 11 nM against JLC. Larger substituents at any position caused a steady decrease in potency, likely due to lowering of DNA binding affinity. A small series of analogues of the most potent bis(5-methylDACA) compound, with second substituents (Me and Cl) in the 1- or 8- position had broadly similar potencies to the 5-Me compound, indicating that, while the 1- and 8-substituents are acceptable, they add little to the enhancing effect of the 5-methyl group. All of the compounds were at least equitoxic (some up to 4-fold more cytotoxic) against the mutant Jurkat lines than in the wild-type, consistent with a relatively greater effect on topoisomerase I compared with topoisomerase II. The bis(5-methylDACA) compound was found to inhibit the action of purified topoisomerase I in a cell-free assay. Compounds were on average 10-fold less cytotoxic in an MCF7 breast cancer line overexpressing P-glycoprotein than in the wild-type line and showed some selectivity for colon tumor lines in the NCI human tumor cell line panel. Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo at substantially lower doses than DACA. The bis(acridine-4-carboxamides) represent a new and interesting class of potent topoisomerase inhibitors.
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PMID:Structure-activity relationships for substituted bis(acridine-4-carboxamides): a new class of anticancer agents. 1039 79

TAS-103 (6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c] quinolin-7-one dihydrochloride), a dual topoisomerase (topo) inhibitor, was developed as an anticancer agent by targeting topo I and topo II and has previously been shown to be effective against lung tumors. In this study, we investigated the cytotoxic activity of TAS-103 in various human cancer cell lines (including gastric, colon, squamous, lung, and breast cancer cells) and the induction of apoptosis by TAS-103. We next established stable transfectants of Bcl-2 in the gastric cancer cell line AZ521 and found that Bcl-2 blocked TAS-103-induced apoptosis. In addition, we demonstrated that the activities of ICE-like and CPP32-like proteases are involved in the signal transduction pathway of TAS-103-induced apoptosis. In summary, TAS-103 is a novel type of anticancer agent with a unique mechanism and could be useful as a lead compound for development of new drugs.
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PMID:A dual topoisomerase inhibitor, TAS-103, induces apoptosis in human cancer cells. 1042 63


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