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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have used stopped-flow spectrophotometry and the sodium dodecyl sulfate sequestration technique to study the kinetics of dissociation of DNA complexes of the mixed topoisomerase I/II poison N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (termed DACA) and a range of related linear tricyclic carboxamides with neutral chromophores. Complexes of DACA and related acridine and phenazinecarboxamides bearing an N,N-dimethylaminoethyl side chain dissociate from calf thymus DNA by a kinetic pathway involving four discernible steps in a manner similar to complexes of N-[(2-dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (termed 9-amino-DACA). We infer from these findings that the side chains of DACA, its phenazine homologue, and 9-amino-DACA make comparable interactions with the DNA base pairs. In the case of 9-amino-DACA, a selective topoisomerase II poison, these are known, by crystallographic analysis, to involve hydrogen-bonding interactions between the protonated dimethylammonium group of the side chain and the O6/N7 atoms of guanine and to include a bridging water molecule hydrogen bonded to the carboxamide group and a phosphate oxygen. By contrast, we find that other linear tricyclic carboxamides with neutral chromophores which lack a peri nitrogen atom and are biologically inactive dissociate from DNA by a different mechanism in which it appears their side chains fail to interact with guanine. We conclude that the ability of the carboxamide group to lie preferentially in the plane of the chromophore, so facilitating the dimethylammonium-guanine hydrogen bond and ensuring maintenance of the water-bridged carboxamide-phosphate interaction, is a critical requirement for antitumor activity among ligands of the linear tricyclic carboxamide class. However, unlike the situation for 9-amino-DACA, for ligands with uncharged chromophores containing peri nitrogen atoms such as DACA, this outcome is possible with the 4-carboxamide group rotated cis or trans with respect to the ring nitrogen. This difference may have relevance to the ability of DACA to be a dual poison of both topoisomerases I and II.
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PMID:Kinetic studies of the binding of acridinecarboxamide topoisomerase poisons to DNA: implications for mode of binding of ligands with uncharged chromophores. 1183 1

Acridine derivatives are one of the oldest classes of bioactives, widely used as antibacterial and antiprotozoal agents. Some work in these areas continues, but recent research has focused mainly on their use as anticancer drugs, because of the ability of the acridine chromophore to intercalate DNA and inhibit topoisomerase enzymes.
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PMID:Acridine derivatives as chemotherapeutic agents. 1217 48

Acridines have been used as chemotherapeutic agents against bacteria, protozoa and fungi, and they now find important use as anticancer drugs. There is a paucity of crystal structures of acridine-DNA complexes above the dinucleotide level, but recent structures of acridinecarboxamide topoisomerase II poisons complexed to hexanucleotides have allowed a molecular rationalization of their structure-activity relationships for cytotoxicity and for their kinetics of DNA binding.
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PMID:Crystal structures of acridines complexed with nucleic acids. 1217 49

We have synthesized two podophyllotoxin-acridine conjugates-pACR6 and pACR8. In these compounds an 9-acridinyl moiety is beta linked to the C4 carbon of the four ring system in 4'-demethylepipodophyllotoxin (epiDPT) via eighter an N-6-aminohexanylamide linker (pACR6) or via an N-8-aminooctanylamide linker containing two more carbon atoms (pACR8). The acridine-linker moiety occupies the position where different glucoside moieties, dispensable for activity, are normally linked to epiDPT in the well known epipodophyllotoxins VP-16 and VM-26. As with VP-16 and VM-26, pACR6 and pACR8 show evidence of being topoisomerase II poisons as they stimulate topoisomerase II mediated DNA cleavage in vitro and induce DNA damage in vivo. This in vivo DNA damage, as well as pACR6/pACR8 mediated cytotoxicity, is antagonized by the catalytic topoisomerase II inhibitors ICRF-187 and aclarubicin, demonstrating that topoisomerase II is a functional biological target for these drugs. Despite their structural similarities, pACR6 was more potent than pACR8 in stimulating topoisomerase II mediated DNA cleavage in vitro as well as DNA damage in vivo and pACR6 was accordingly more cytotoxic towards various human and murine cell lines than pACR8. Further, marked cross-resistance to pACR6 was seen among a panel of multidrug-resistant (MDR) cell lines over-expressing the MDR1 (multidrug resistance protein 1) ABC drug transporter, while these cell lines remained sensitive towards pACR8. pACR8 was also capable of circumventing drug resistance among at-MDR (altered topoisomerase II MDR) cell lines not over-expressing drug transporters, while pACR6 was not. Two resistant cell lines, OC-NYH/pACR6 and OC-NYH/pACR8, were developed by exposure of small cell lung cancer (SCLC) OC-NYH cells to gradually increasing concentrations of pACR6 and pACR8, respectively. Here, OC-NYH/pACR6 cells were found to over-express MDR1 and, accordingly, displayed active transport of 3H-labeled vincristine, while OC-NYH/pACR8 cells did not, further suggesting that pACR6, but not pACR8, is a substrate for MDR1. Our results show that the spatial orientation of podophyllotoxin and acridine moieties in hybrid molecules determine target interaction as well as substrate specificity in active drug transport.
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PMID:Linker length in podophyllotoxin-acridine conjugates determines potency in vivo and in vitro as well as specificity against MDR cell lines. 1237 83

DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride) has high experimental antitumor activity and has completed phase I/II clinical trials. It targets both topoisomerase (topo) I and II, but the roles of each of these enzymes in the antitumour action of DACA are not known. We have used a series of DACA analogues (mainly monosubstituted halogen derivatives) to relate in vitro and in vivo biological activity. We measured topo II selectivity by comparing the inhibition of Jurkat human leukaemia cell lines with high and low topo II content. We determined survival curves following exposure of H460 human lung carcinoma cells for 1 h. We used plasmid DNA to compare the effects of DACA analogues on isolated topo I and II, measuring in particular the inhibition of topo I- and II-mediated DNA relaxation. The results indicate that 5-halogen substituted derivatives are the most active in clonogenic cytotoxicity assays and that this activity is related to their selective activity towards Jurkat cells with high topo II activity. In isolated topo assays, 5-halogen substituted derivatives were also the most potent and in each case the concentration required for inhibition of topo II relaxation was greater than that for inhibition of topo I relaxation. The drug concentration providing efficient cytotoxicity corresponded to that which suppressed the activity of topo I but not of topo II. We hypothesize that DACA analogues act both in vitro and in vivo to simultaneously poison topo II and inhibit topo I catalytic activity, and that this combination contributes to the high antitumour activity of DACA analogues.
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PMID:Topoisomerase I/II selectivity among derivatives of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA). 1237 84

The differentiating agent and histone deacetylase inhibitor, sodium butyrate (NaB), was shown previously to cause a transient, 3-17-fold induction of human DNA topoisomerase II alpha (topo II alpha) gene promoter activity and a 2-fold increase in topo II alpha protein early in monocytic differentiation of HL-60 cells. This observation has now been extended to other short chain fatty acids and aromatic butyrate analogues, and evidence is presented that human topo II alpha promoter induction correlates closely with histone H4 acetylation status. Because increased topo II alpha expression is associated with enhanced efficacy of topo II-poisoning antitumor drugs such as etoposide, the hypothesis tested in this report was whether NaB pretreatment could sensitize HL-60 myeloid leukemia and K562 erythroleukemia cells to etoposide-triggered DNA damage and cell death. A 24-72 h NaB treatment (0.4-0.5 mM) induced topo II alpha 2-2.5-fold in both HL-60 and K562 cells and caused a dose-dependent enhancement of etoposidestimulated, protein-linked DNA complexes in both cell lines. At concentrations with minimal effects on cell cycle kinetics (0.4 mM in HL-60; 0.5 mM in K562), NaB pretreatment also modestly enhanced etoposidetriggered apoptosis in HL-60 cells, as determined morphologically after acridine orange/ethidium bromide staining, and substantially increased K562 growth inhibition and poly(ADP-ribose)polymerase cleavage after etoposide exposure. Therefore, a temporal window may exist whereby a differentiating agent may sensitize experimental leukemias to a cytotoxic antitumor agent. These results indicate that histone deacetylase inhibitors should be investigated for etoposide sensitization of other butyrate-responsive hematopoietic and nonhematopoietic tumor lines in vitro and in vivo.
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PMID:The histone deacetylase inhibitor sodium butyrate induces DNA topoisomerase II alpha expression and confers hypersensitivity to etoposide in human leukemic cell lines. 1246 29

Amsacrine is an acridine derivative drug applied in haematological malignancies. It targets topoisomerase II enhancing the formation of a cleavable DNA-enzyme complex and leading to DNA fragmentation in dividing cancer cells. Little is known about other modes of the interaction of amsacrine with DNA, by which it could affect also normal cells. Using the alkaline comet assay, we showed that amsacrine at concentrations from the range 0.01 to 10 microM induced DNA damage in normal human lymphocytes, human promyelocytic leukemia HL-60 cells lacking the p53 gene and murine pro-B lymphoid cells BaF3 expressing BCR/ABL oncogene measured as the increase in percentage tail DNA. The effect was dose-dependent. Treated cells were able to recover within a 120-min incubation. Amifostine at 14 mM decreased the level of DNA damage in normal lymphocytes, had no effect on the HL-60 cells and potentiated the DNA-damaging effect of the drug in BCR/ABL-transformed cells. Vitamin C at 10 and 50 microM diminished the extent of DNA damage in normal lymphocytes, but had no effect in cancer cells. Pre-treatment of the cells with the nitrone spin trap, N-tert-butyl-alpha-phenylnitrone or ebselen, which mimics glutathione peroxidase, reduced the extent of DNA damage evoked by amsacrine in all types of cells. The cells exposed to amsacrine and treated with endonuclease III and 3-methyladenine-DNA glycosylase II, the enzymes recognizing oxidized and alkylated bases, respectively, displayed greater extent of DNA damage than those not treated with these enzymes. The results obtained suggest that free radicals may be involved in the formation of DNA lesions induced by amsacrine. The drug can also methylate DNA bases. Our results indicate that the induction of secondary malignancies should be taken into account as diverse side effects of amsacrine. Amifostine may potentate DNA-damage effect of amsacrine in cancer cells and decrease this effect in normal cells and Vitamin C can be considered as a protective agent against DNA damage in normal cells.
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PMID:Free radical scavengers can differentially modulate the genotoxicity of amsacrine in normal and cancer cells. 1254 80

While the majority of topoisomerase (topo) inhibitors show selectivity against either topo I or topo II, a small class of compounds can act against both enzymes. These can be divided into three classes. The first and largest class comprise drugs that bind to DNA by intercalation and include the clinically-evaluated acridine DACA, the benzopyridoindole intoplicine, the indenoquinolinone TAS-103, the benzophenazine XR11576, and the pyrazoloacridine NSC 366140. The second category comprises hybrid molecules, prepared by physically linking separate inhibitors of topo I and topo II, or by linking pure topo inhibitors to other DNA-interactive carriers. While several derivatives (e.g., camptothecin-epipodophyllotoxin and ellipticine-distamycin hybrids) have been prepared, there have been no detailed studies. The third category are less well defined as a structural class, but apparently recognize structural motifs that are present in both topo I and II enzymes. These include a series of benzoisoquinolinium quaternary salts such as NK 109, and more interestingly modified versions of classical topo I or topo II inhibitors; e.g., the modified camptothecin BN 80927 and the modified epipodophyllotoxin tafluposide (F-11782). There is as yet no detailed understanding of the factors that result in selective or dual inhibition, but structure-activity studies in several classes show that structural changes can influence topo I/II selectivity. DNA intercalation mode also appears to play a part. The basis for the high antitumor activity of some topo inhibitors is not yet understood but may depend on the complex pattern of activities that include both inhibition and poisoning of the two enzymes.
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PMID:Dual topoisomerase I/II inhibitors in cancer therapy. 1257 Jul 67

The aim of the study was to investigate the antitumor and/or preventive effect of BC-4, an isomeric compound isolated from the plant Boswellia carteri Birdw. containing alpha- and beta-boswellic acid acetate in 1:1, MW 498.3. We used the MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide) assay to study the growth inhibition activity of BC-4. Tumor cells migration within a three-dimensional collagen matrix was recorded by time-lapse videomicroscopy and computer-assisted cell tracking. Topoisomerase II was isolated from mouse melanoma B16F10 cells and its activity was determined by its ability to cut plasmid pBR322 DNA. The secretion and activity of matrix metalloproteinases (MMPs) from human fibrosarcoma HT-1080 cells were determined by gelatin zymography. BC-4 was a cytostatic compound and could induce the differentiation of B16F10 mouse melanoma cells, blocked the cell population in G1 phase and inhibited topoisomerase II activity. The G1 phase population of B16F10 cells was increased from 57.4 to 87.7%, while S phase population was reduced from 33.3 to 5.9% after treatment with BC-4 at 25 microM concentration for 48 h. BC-4 also inhibited the migration activity of B16F10. BC-4 could induce apoptosis of HT-1080 cells, as proved by acridine orange fluorescence staining, Wright-Giemsa staining, electromicroscopy, DNA fragmentation and flow cytometry. BC-4 inhibited the secretion of MMPs from HT-1080 cells, too. In conclusion, if it turns out that BC-4 is a well tolerated substance, exhibiting no significant toxicity or side effects, being evaluated currently in China, BC-4 is a good candidate for the prevention of primary tumor, invasion and metastasis.
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PMID:Boswellic acid acetate induces differentiation and apoptosis in highly metastatic melanoma and fibrosarcoma cells. 1260 Apr 19

There is considerable interest in the development of sequence-selective DNA drugs. Chemical agents able to interfere with DNA topoisomerases - essential nuclear enzymes- are widespread in nature, and some of them have outstanding therapeutic efficacy in human cancer and infectious diseases. Several classes of antineoplastic drugs, such as amsacrine, daunorubicin, etoposide (acting on type II topoisomerases), camptothecin and indolocarbazole derivatives of the antibiotic rebeccamycin (acting on type IB topoisomerases), have been shown to stimulate DNA cleavage by topoisomerases leading to cell death. However, these molecules exhibit little sequence preference. A convenient strategy to confer sequence specificity consists in the attachment of these topoisomerase poisons to sequence-specific DNA binding elements. Among sequence-specific DNA ligands, oligonucleotides can bind with high specificity of recognition to the major groove of double-helical DNA, resulting in triple helix formation. In this context, derivatives of camptothecin, indolocarbazole, anthracycline and acridine poisons have been covalently tethered to triple helix-forming oligonucleotides. The use of triple-helical DNA structures offers an efficient system to target topoisomerase I and II-mediated DNA cleavage to specific sequences and to increase the drug efficacy at these sites. Chemical optimization of the conjugates is essential to the efficacy of drug targeting. Consequently, the rational design of this new class of anti-cancer agents, conceived from topoisomerase poisons and triplex-forming oligonucleotides, may be exploited to improve the efficacy and selectivity of the DNA damage induced by topoisomerases.
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PMID:Design of new anti-cancer agents based on topoisomerase poisons targeted to specific DNA sequences. 1267 55


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