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)

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA), a DNA intercalator that exerts its antitumour action through the enzyme topoisomerase II, has previously been shown to be curative against the transplantable Lewis lung adenocarcinoma growing as lung tumour nodules in mice. On the basis of this finding as well as its high in vitro activity against multidrug-resistant cell lines, DACA has been chosen for clinical trial under the auspices of the Cancer Research Campaign, United Kingdom. In the present study the activity of DACA was assessed against advanced (5-mm diameter) s.c. colon 38 adenocarcinomas in BDF1 mice using tumour-growth delay as an end point. Its activity was found to be related positively to the total dose given and negatively to the total duration of the dose schedule. Adoption of a split-dose i.p. administration schedule or slow i.v. infusion allowed the administration of large doses without toxicity. The activity of DACA was comparable with that of 5-fluorouracil and superior to that of doxorubicin, cyclophosphamide and the experimental amsacrine analogue CI-921. Mitoxantrone, amsacrine, etoposide, teniposide and daunorubicin showed minimal activity. DACA also demonstrated significant activity against the NZM3 melanoma human cell line growing as a xenograft in athymic mice.
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PMID:Experimental solid tumour activity of N-[2-(dimethylamino)ethyl]-acridine-4-carboxamide. 778 Nov 46

A growth factor-dependent cell line (TF-1) was treated with interleukin-3 (IL-3) or medium in combination with variable doses of VP-16 to test whether the latter's cytotoxicity can be modulated by IL-3. The results demonstrated that an augmented cell death occurred with TF-1 cells when pre-incubated for 24 h with IL-3 followed by treatment with VP-16 (10 micrograms/ml) for 1 h. The increased cell death could not be ascribed to an increased number of apoptotic cells as measured with the acridine orange method. However, the IL-3 treatment coincided with an upregulation of DNA topoisomerase II alpha (Topo II alpha) at mRNA and protein level after 24 h, which was preceded by an upregulation of c-myc mRNA. In contrast, Topo II beta did not demonstrate an upregulation at mRNA level in response to IL-3 stimulation. In addition, it was shown that cells treated with IL-3 followed by VP-16 demonstrated a higher number of cleavable DNA complexes which was not due to an increased uptake of VP-16, since cellular concentrations of VP-16 in the presence of IL-3 or medium were 16.8 +/- 7.8 ng/10(6) cells and 19.8 +/- 7.8 ng/10(6) cells (mean +/- SD, n = 3), respectively. These data indicate that IL-3 pretreatment followed by VP-16 results in an increased cell death due to cytotoxicity which may be ascribed to an upregulation of Topo II alpha.
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PMID:VP-16-mediated cytotoxicity is modulated by interleukin-3 in a growth factor-dependent leukemic cell line. 780 95

Acridine-induced frameshift mutagenesis in bacteriophage T4 has been shown to be dependent on T4 topoisomerase. In the absence of a functional T4 topoisomerase, in vivo acridine-induced mutagenesis is reduced to background levels. Further, the in vivo sites of acridine-induced deletions and duplications correlate precisely with in vitro sites of acridine-induced T4 topoisomerase cleavage. These correlations suggest that acridine-induced discontinuities introduced by topoisomerase could be processed into frameshift mutations. The induced mutations at these sites have a specific arrangement about the cleavage site. Deletions occur adjacent to the 3' end and duplications occur adjacent to the 5' end of the cleaved bond. It was proposed that at the nick, deletions could be produced by the 3'-->5' removal of bases by DNA polymerase-associated exonuclease and duplications could be produced by the 5'-->3' templated addition of bases. We have tested in vivo for T4 DNA polymerase involvement in nick processing, using T4 phage having DNA polymerases with altered ratios of exonuclease to polymerase activities. We predicted that the ratios of the deletion to duplication mutations induced by acridines in these polymerase mutant strains would reflect the altered exonuclease/polymerase ratios of the mutant T4 DNA polymerases. The results support this prediction, confirming that the two activities of the T4 DNA polymerase contribute to mutagenesis. The experiments show that the influence of T4 DNA polymerase in acridine-induced mutation specificities is due to its processing of acridine-induced 3'-hydroxyl ends to generate deletions and duplications by a mechanism that does not involve DNA slippage.
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PMID:DNA nick processing by exonuclease and polymerase activities of bacteriophage T4 DNA polymerase accounts for acridine-induced mutation specificities in T4. 789 53

The DNA binding properties and effects on topoisomerase II of MePyGA, an anilinoacridine derivative bearing an N-methylpyrrolecarboxamide unit at position 1', have been compared with those of its precursor glycylanilinoacridine and the structurally related antileukaemic drug amsacrine. Electric linear dichroism spectroscopy reveals that MePyGA intercalates its acridine chromophore between DNA base pairs with a preference for GC-rich sequences, whereas both its structural analogue lacking the N-methylpyrrole unit and amsacrine intercalate into DNA without any strong sequence preference. The effects of the test drug on the catalytic activities of topoisomerase II were studied in vitro using purified calf thymus enzyme and 32P-labeled DNA. MePyGA stabilizes the topoisomerase II-DNA covalent complex and stimulates the cutting of DNA at a subset of preexisting topoisomerase II cleavage sites. The removal of the N-methylpyrrole unit abolishes both the GC-preferential binding to DNA and the topoisomerase II-mediated DNA cleavage. MePyGA and amsacrine stimulate the cleavage of DNA by topoisomerase II at different places: cleavage stimulated by amsacrine is consistent with the expected adenine requirement at position +1 whereas the predominant sites of DNA cleavage stimulated by MePyGA contain a cytosine at position +/- 1. This is the first instance where an anilinoacridine derivative differing only by the nature of the substituent at position 1' has been found to affect the catalytic activity of topoisomerase II differently. The spectroscopic and biochemical data lead to the conclusion that two functional domains can be identified in MePyGA: its anilino group can be regarded as a skeletal core to which are connected (i) the tricyclic acridine moiety which represents the DNA-binding domain and (ii) the N-methylpyrrole moiety which constitutes the topoisomerase II-targeted domain. The structure of the substituent at position 1' of the anilinoacridine chromophore evidently determines the location of the sites of DNA cleavage by topoisomerase II. These findings provide guidance for the synthesis and development of new topoisomerase II-targeted antitumor anilinoacridine derivatives.
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PMID:Stimulation of site-specific topoisomerase II-mediated DNA cleavage by an N-methylpyrrolecarboxamide-anilinoacridine conjugate: relation to DNA binding. 806 Sep 93

A number of topoisomerase II-acting drugs have been described, but few demonstrate schedule-dependent anti-tumour activity. The activity of the epipodophyllotoxins etoposide and teniposide and the acridine dye derivative amsacrine is clearly schedule-dependent, and this related not only to the observation that the activity of topoisomerase II varies throughout the cell cycle but also to the finding that these drugs are rapidly cleared from the cell following exposure, permitting DNA repair. Etoposide has been most clearly shown to be schedule dependent in clinical studies. The response rates of patients with small-cell lung cancer receiving a 24-h infusion was only 10% as compared with 89% when the same dose was given over 5 days. Pharmacokinetic studies performed in these patients demonstrated that although the total systemic exposure (area under the plasma concentration-time curve, AUC) was the same in both arms of the study, the duration of exposure to low levels of drug (> 1 microgram/ml) was doubled in the 5-day arm. Haematological toxicity was the same in both arms of the study, as was the duration of exposure to higher plasma levels (> 5 micrograms/ml), suggesting that this toxicity may be associated with higher plasma concentrations, whereas anti-tumour activity is related to prolonged exposure to low levels of drug. This was confirmed in a subsequent study, where prolongation of treatment to 8 days compared to 5 days resulted in a similar exposure to low plasma concentrations and no difference in response rates or survival. Haematological toxicity in this study was worse in the 5-day arm, which also had an increase exposure to high levels of drug (> 5 micrograms/ml). More recently, interest has focused on even more prolonged etoposide administration, typically involving small daily doses repeated for 14-21 days. Although this schedule shows high activity in relapsed small-cell lung cancer and lymphoma, it is associated with significant toxicity (around one-third of patients experience grade III/IV leukopenia or neutropenia), which may be related to the observation that the etoposide dose delivered per course in these studies is higher than that obtained with standard dosing over 3-5 days. Further randomised studies are required to determine the optimal dose and schedule of etoposide.
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PMID:Schedule-dependent topoisomerase II-inhibiting drugs. 807 33

Acridine-4-carboxamide and 2-(4-pyridyl)quinoline-8-carboxamide represent a new generation of antitumor intercalators related to amsacrine (m-AMSA), a classic topoisomerase II-targeted drug. We examined the ability of these tricyclic carboxamides to induce DNA lesions that reflect the stabilization of topoisomerase II cleavage complexes. DNA-protein cross-links (DPC) and DNA double-strand breaks (DSB) were assessed in mouse fibrosarcoma cells (line 935.1). DPC were rapidly formed and readily reversible. A bell-shape concentration dependence suggested a self-inhibition of DPC at higher drug levels. In isolated nuclei, DPC formation by 2-(4-pyridyl)quinoline-8-carboxamide required ATP and was inhibited by novobiocin, a topoisomerase II inhibitor. Acridine-4-carboxamide and 2-(4-pyridyl)quinoline-8-carboxamide were also potent inducers of DSB. In contrast to DPC, however, DNA breaks continued to increase with drug concentration. These DSB were masked (presumably by non-covalently associated proteins) when analyzed by nucleoid sedimentation. Thus, while both DPC and DSB seemed to be topoisomerase mediated, at least some DSB appeared to lack the enzyme bound covalently. DNA lesions by tricyclic carboxamides occurred, in general, at drug concentrations comparable to those needed to inhibit cell survival. Also, the tricyclic carboxamides inhibited the catalytic activity of isolated topoisomerase II. The results indicate that tricyclic carboxamides interfere with the action of topoisomerase II. However, the mechanisms of enzyme inhibition by these drugs differ from the classical trapping of topoisomerase in covalent cleavage complex m-AMSA.
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PMID:Topoisomerase II mediated DNA lesions induced by acridine-4-carboxamide and 2-(4-pyridyl)quinoline-8-carboxamide. 814 68

A series of 9-anilinoacridines have been prepared and evaluated for their activity against a multidrug-resistant K1 strain of the malaria parasite Plasmodium falciparum in erythrocyte suspensions. 3,6-Diamino substitution on the acridine ring resulted in lower mammalian cell cytotoxicity and higher antiparasitic activity than other substitution patterns, providing compounds with the highest in vitro therapeutic indices. A new synthesis of 3,6-diamino-9-anilinoacridines, via reduction of the corresponding diazides, gives much higher yields than traditional methods. Within the subset of 3,6-diamino-9-anilinoacridines, there was considerable tolerance to substitution at the 1'-anilino position. In a sharp divergence with structure-activity relationships for high mammalian cell toxicity and anticancer effects, derivatives bearing electron-withdrawing 1'-substituents (e.g., SO2-NHR and CONHR) showed the most potent antimalarial activity (IC50 values of 10-20 nM). Representative compounds were shown to be potent inhibitors of the DNA strand-passing activity of human topoisomerase II and of the DNA decatenation activity of the corresponding parasite enzyme. The 1'-SO2NH2derivative 7n completely inhibited strand passage by Jurkat topoisomerase II at 20 microM, and an increase in linear DNA (indicative of inhibition of religation) was seen at or above 1 microM. It also inhibited the decatenating activity of the parasite topoisomerase II at 6 microM and above. In contrast, the analogous compound without the 3,6-diamino substituent was inactive in both assays up to 100 microM. Overall, there was a positive relationship between the ability of the drugs to inhibit parasite growth in culture and their ability to inhibit parasite topoisomerase II activity in an isolated enzyme assay. The 1'-SO2NH2 derivative 7n showed a high IVTI (1000) and was a potent inhibitor of both P. falciparum in vitro (IC50 20 nM) and P. falciparum-derived topoisomerase II. However, the compound was inactive against Plasmodium berghei in mice; reasons may include rapid metabolic inactivation (possibly by N-acetylation) and/or poor distribution.
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PMID:Synthesis and in vitro evaluation of 9-anilino-3,6-diaminoacridines active against a multidrug-resistant strain of the malaria parasite Plasmodium falciparum. 818 7

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (DACA) is a topoisomerase II-directed DNA intercalator with high experimental solid-tumour activity. The effect of DACA on the cytokinetics of cultured Lewis lung adenocarcinoma cells was compared with those of two clinical drugs of this class, doxorubicin and amsacrine. Cells were exposed to drugs for a 1-h period at concentrations that reduced viability by approximately 99% as measured by clonogenic assays. Subsequent progress through the cell cycle was monitored by propidium staining of fixed cells and flow cytometry. DACA, amsacrine and doxorubicin did not inhibit the G1- to S-phase transition but did delay progression through the S-phase. The effect was maximal in the late S-phase and, because of the differential rates of progress of cells in various cycle positions, led to the development of a synchronous S-phase peak. This peak moved to the G2/M-phase position at 11 h after the removal of DACA or at 14 h after the removal of amsacrine or doxorubicin. The effects of the drugs on cells initially in the G2-phase was measured by scoring mitotic cells in the presence and absence of colchicine. DACA had an immediate inhibitory effect on the progression of cells from the G2-phase to mitosis. This effect was much greater for DACA than for the other two drugs, consistent with the greater effect of DACA on the G2/M-phase to G1-phase transition. The results suggest that DACA causes cell-cycle changes expected for a DNA-damaging drug but differs from doxorubicin and amsacrine mainly by its effect on the transition of G2-phase cells to mitosis and the G1-phase.
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PMID:Cytokinetic differences in the action of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide as compared with that of amsacrine and doxorubicin. 825 95

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

The successful treatment of cancer requires the identification of new drugs with novel actions. N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (DACA) is a topoisomerase II-targeted antitumour drug with curative activity against murine Lewis lung carcinoma. DACA was assessed for novel patterns of growth inhibition using normal and multidrug-resistant human cell lines. Cells were cultured in 96-well microtitre trays and tested against DACA and related topoisomerase-directed drugs, including amsacrine, etoposide and doxorubicin, and drug concentrations for 50% growth inhibition (IC50 or GI50 values) were determined. In a series of Jurkat leukaemia lines characterised as exhibiting atypical multidrug resistance, DACA was to a large extent capable of overcoming multidrug resistance exhibited towards the other topoisomerase-directed agents. DACA was also tested against the National Cancer Institute 60-tumour-specific cell-line panel (GI50 values ranging from 420 to 5,400 nM; mean, 2,100 nM) and against a series of primary cultures of surgically excised melanomas (IC50 values ranging from 60 to 1,600 nM; mean, 590 nM). DELTA values (deviations of logarithmic IC50 or GI50 values from the mean) were calculated and compared by correlation analysis. The standard deviation of DELTA values was found to be lower for DACA than for the other topoisomerase II-directed drugs amsacrine, etoposide, doxorubicin and mitozantrone in both the cell lines and the primary cultures. These lower standard deviations appear to have resulted from the reduced susceptibility of DACA to both P-glycoprotein- and topoisomerase II-mediated multidrug-resistance mechanisms occurring naturally in cell lines and primary cultures.
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PMID:In vitro assessment of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide, a DNA-intercalating antitumour drug with reduced sensitivity to multidrug resistance. 838 21


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