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At least 19 recordsLinked to original sources

PubMed1993

Are lethal effects of nitracrine on L5178Y cell sublines associated with DNA-protein crosslinks?

Nitracrine (Ledakrin, 1-nitro-9-(3,3-N,N-dimethylaminopropylamino)-acridine) is of interest as a DNA intercalator and alkylator with very high cytotoxic potency, especially against hypoxic cells. DNA-DNA crosslinks [Konopa et al., Chem Biol Interact 43: 175-197, 1983; Pawlak et al., Cancer Res 44: 4289-4296, 1984] or DNA-protein crosslinks (DPCs) [Woynarowski et al., Biochem Pharmacol 38: 4095-4101, 1989; Szmigiero and Studzian, Biochim Biophys Acta 1008: 339-345, 1989] are related to the toxicity of the drug. The cytotoxic effect of and DNA damage induced by nitracrine were measured in two sublines of mouse lymphoma L5178Y, LY-R (resistant to ionizing radiation) and LY-S (sensitive to ionizing radiation). LY-R cells were more sensitive to nitracrine (D10 = 0.11 microM) than LY-S (D10 = 0.35 microM) when treated for 1 hr at 37 degrees. To a DNA-DNA crosslinking agent, mitomycin C, the comparative sensitivity was opposite. LY-R cells were more resistant to this drug than LY-S cells (D10 = 7.1 vs 2.3 microM). DNA damage induced by nitracrine was measured by the alkaline elution method and by nitrocellulose filter binding assay. Nitracrine treatment with biologically relevant concentrations (0.1-3.0 microM, 1 hr, 37 degrees) induced only DPCs. Interstrand crosslinks and DNA breaks were not detected. Nitracrine produced about two times more DPCs in LY-R cells than in LY-S cells. Both sublines removed 50% of initial lesions during 2 hr post-treatment incubation. The greater sensitivity of LY-R cells to nitracrine is thus not related to the efficiency of DNA repair, but may be a consequence of enhanced initial damage in the form of DPCs. This finding is consistent with the latter lesion being responsible for the cytotoxicity of nitracrine.

Animals↗

PubMed1984

Effect of intercalating and groove-binding ligands on formation of covalent complexes between nitracrine (Ledakrin, C-283) or 8-methoxypsoralen and DNA.

The effect of ethidium bromide, actinomycin D, distamycin A and netropsin on covalent binding of nitracrine (1-nitro-9-(3,3-N,N-dimethylaminopropylamino)acridine, Ledakrin, C-283) and 8-methoxypsoralen to DNA was examined. The competition was assayed either directly with [3H]- and [14C]nitracrine or indirectly by estimation of transcriptional template activity of nitracrine-DNA and 8-methoxypsoralen-DNA complexes formed in the presence of the ligands. A higher protective effect of ethidium bromide and distamycin on the photo-binding of 8-methoxypsoralen than on the dithiothreitol-dependent attachement of nitracrine to DNA assayed at 0.15 M KCl or NaCl was observed. The non-intercalating antibiotics showed lower competitive effect on 8-methoxypsoralen binding than ethidium bromide. Actinomycin D showed relatively low competition for both drugs with DNA. In contrast to the reaction of 8-methoxypsoralen, the decrease of nitracrine binding in the presence of competing ligands considerably depends on ionic strength. Particularly high inhibition of the adduct formation in the presence of ethidium at 1 M KCl was shown, while the amount of nitracrine bound in the presence of distamycin increases at elevated ionic strength. The results may indicate steric demands of the reaction between nitracrine and DNA.

Aminoacridines↗

PubMed1987

Anaerobic incubation and mutagenicity of nitracrine analogues in Salmonella typhimurium.

Nitracrine [1-nitro-9-(dimethylaminopropylamino)-acridine] is a clinical antitumour agent with hypoxia-selective cytotoxicity and radiosensitizing activity. Developments in tumour therapy using either nitracrine itself or some of its analogues under development are likely to be targeted at anaerobic regions of tumours. We have investigated the effects of anaerobiosis on mutagenic activity of nitracrine and a small series of analogues in three derivatives of Salmonella typhimurium frameshift strain hisC3076. Nitracrine-induced mutagenicity was apparently enhanced by a period of anaerobic incubation followed by an aerobic period, with maximal mutagenic effectiveness (as revertants/nmol) being seen at 24 h anaerobiosis. However, the maximal number of nitracrine-induced revertants was not increased by anaerobic incubation, and the relationship between mutagenicity and toxicity remained similar. Comparisons of the effects of anaerobiosis on mutagenicity of bacterial strains with different DNA repair capacities suggested that anaerobiosis was not simply depressing 'SOS' repair. Comparisons of nitracrine with four of its analogues showed that this effect was not a universal characteristic of either acridine derivatives or of nitracrine analogues. Rather, the dose displacements obtained paralleled hypoxic cell selective cytotoxicity in mammalian cells. If this result extends to other compounds, experiments of this nature using the bacterial strains could provide a novel and useful screening system to identify hypoxia-selective cytotoxic anticancer drugs of potential clinical value.

Aminoacridines↗

PubMed1989

Hypoxia-selective antitumor agents. 2. Electronic effects of 4-substituents on the mechanisms of cytotoxicity and metabolic stability of nitracrine derivatives.

The mechanism of cytotoxicity of a series of 4-substituted derivatives of 9-[[3-(dimethylamino)propyl]amino]-1-nitroacridine (nitracrine) has been studied, using a panel of DNA repair-defective mutants of the Chinese hamster ovary cell line AA8. Cell lines UV-4 and UV-5 were hypersensitive to nitracrine, with sensitivities approximately 10-fold greater than that of AA8, while EM-9 showed a hypersensitivity factor (HF) of about 2-fold. This pattern suggests the major cytotoxic lesions induced by nitracrine are bulky DNA monoadducts, rather than DNA interstrand cross-links as previously suggested. The desnitro analogue of nitracrine, which retains the intercalative potential of the latter but cannot be metabolically activated by nitro reduction, showed no hypersensitivity, indicating the specificity with which this panel of cell lines can discriminate different types of DNA damage. Several of the highly cytotoxic 4-substituted nitracrine derivatives showed HFs similar to that of the parent, but the less potent 4-dialkylamino and 4-COOMe derivatives showed much lower HFs for UV-4, suggesting that different mechanisms of cytotoxicity contribute. All compounds showed similar HFs under both aerobic and hypoxic conditions, indicating that hypoxia-selective toxicity in this series is due to a quantitative rather than qualitative change in the presence of oxygen. Rates of metabolic consumption of the compounds were measured under both aerobic and hypoxic conditions by bioassay against the sensitive UV-4 cell line. The results agreed well with previous inferences on metabolic stability derived from cell-killing kinetics and showed that electron-donating 4-substituents can be used to increase metabolic stability in vitro. Such stabilization may enhance the therapeutic utility of the nitroacridines in cancer therapy since rapid metabolism of nitracrine appears to prevent its activity against hypoxic cells in solid tumors.

Aminoacridines↗

PubMed2002

Modulation of G(2) arrest enhances cell death induced by the antitumor 1-nitroacridine derivative, Nitracrine.

Nitracrine (Ledakrin) is an antitumor drug which is activated by cellular enzymes and binds covalently to DNA. Previous studies have shown that covalent binding and crosslinking of DNA is associated with the cytotoxic and antitumor activities of this compound. In this study, cell cycle perturbations, effects on DNA synthesis and the cell death process initiated by Nitracrine were studied in murine leukemia L1210 cells. We show that exposure of L1210 cells to Nitracrine at the IC(99) concentration delayed progression through the S phase and transiently arrested cells in G(2)/M as found by flow cytometry. Higher drug concentration (2 x IC(99)) inhibited cell cycle progression in the S phase and induced rapid cell death. Both studied concentrations of the drug produced different effects on DNA synthesis as determined by bromodeoxyuridine incorporation, with a delay in the S phase progression at EC(99) concentration and irreversible arrest in early S phase at the higher dose (2 x IC(99)). At both concentrations of Nitracrine cell death occurred preferentially in the S phase as revealed by the TUNEL assay. When cells treated with the drug for 4 hours were post-incubated in the presence of 1 mM caffeine this led to rapid cell death and suppression of the G(2) arrest. This was associated with a about 10-fold increase in the cytotoxicity of Nitracrine. Similar effects were observed for another DNA crosslinking agent, cis-platinum, and to a lesser extent, for DNA topoisomerase I inhibitor, camptothecin. Together, our studies show that suppression of G(2) arrest induced by Nitracrine greatly enhances its cytotoxicity toward L1210 cells.

Apoptosis↗

PubMed1989

Mutagenesis by the anti-tumour drug nitracrine in Escherichia coli.

The antitumour drug nitracrine [1-nitro-9-(dimethylaminopropylamino)acridine], known to be a potent frameshift mutagen in strains of Salmonella typhimurium, also strongly reverts the lacZ19124 frameshift marker in Escherichia coli. The results in E. coli indicate that nitracrine causes DNA damage which can be excised by the UvrA,B,C excinuclease, can generate mutations by a recA-dependent mechanism, and gives enhanced yields of mutants when plasmid pKM101 is present. Despite these observations, mutagenesis by nitracrine appears to be independent of the UmuC gene product, and hence nitracrine differs from most (but not all) other chemicals which generate mutations via the SOS response. Given that umuC mutants are about as mutable by nitracine as the wild-type parent strain, it is somewhat surprising that plasmid pKM101 causes an enhancement of nitracrine mutagenesis. Nevertheless, we have found that the observed enhancement of mutagenesis by pKM101 is a function of the mucB gene, normally assumed to be essentially homologous to the umuC gene.

Aminoacridines↗

PubMed1984

Selective toxicity of nitracrine to hypoxic mammalian cells.

Hypoxic cells in solid tumours are resistant to ionizing radiation and may be refractory to treatment by many chemotherapeutic agents. For these reasons the identification of drugs with selective toxicity towards hypoxic cells is an important objective in cancer chemotherapy. Nitroimidazoles such as misonidazole demonstrate such hypoxia-selective toxicity but have very low dose potency. The 1-nitroacridine derivative 1-nitro-9-(dimethylaminopropylamino)acridine (nitracrine) binds reversibly to DNA but also forms covalent adducts with DNA in vivo. We have found nitracrine to be selectively toxic to the Chinese hamster ovary cell line AA8 under hypoxic conditions in culture, with a potency approximately 100,000 times higher than that of misonidazole. The effect of oxygen is not a simple dose-modifying one in this system, probably in part because of rapid metabolic inactivation of nitracrine under hypoxic conditions. Viscometric studies with the mini col E1 plasmid PML-21 confirmed that nitracrine binds to DNA by intercalation, and provided an unwinding angle of 16 degrees (relative to 26 degrees for ethidium). It is proposed that the cytotoxicity of nitracrine under hypoxia is due to reductive metabolism to form an alkylating species, but that intercalation of the chromophore may enhance reactivity towards DNA and hence contribute to the marked enhancement of potency with respect to simple nitroheteroaromatic drugs.

Aminoacridines↗

PubMed1989

Mutagenic activity of nitracrine derivatives in Salmonella typhimurium: relationship to drug physicochemical parameters, and to bacterial uvrB and recA genes and plasmid pKM101.

To determine whether it is possible to separate antitumour and mutagenic properties in the nitracrine series, a number of 4-substituted derivatives of the hypoxia-selective drug nitracrine have been evaluated for their mutagenic effects at three loci in several strains of Salmonella typhimurium differing in DNA-repair capacity (uvrB, recA, plasmid pKM101). The drugs divided into two series in terms of their biological effects. Group A compounds (nitracrine and its Cl, F, Me and OMe derivatives) were very toxic to bacteria, and uvrB and recA deletions enhanced toxicity by 10-80-fold. Mutagenic potency was high, being slightly enhanced by uvrB and reduced by recA deletions. In contrast the toxicities and mutagenic potentials of Group B compounds (COOMe, NMe2, and two other bulky amine derivatives) were reduced by at least an order of magnitude, with uvrB and recA deletions showing lesser influence. The COOMe derivative was the only compound showing greater effects at the hisC3076 locus than the hisD3052 or hisG46 loci. The data suggest that all the compounds cause mutations through intercalation and/or monoadduct formation, but only for the COOMe derivative is intercalation the dominant mode of action. Group A compounds appear to have the additional ability to cross-link DNA, a property which amounts for their high potency but which is not compatible with bulky 4-substituents. Apart from these generalizations, there was considerable variation in mutagenic efficiency (as measured by the maximum numbers of revertant colonies) within each series. Of the compounds studied, the 4-OMe derivative appears to best retain the desirable antitumour properties of nitracrine while showing greatly-reduced mutagenic potential, and is an interesting lead for further development.

Aminoacridines↗

PubMed1987

Comparison of antitumor properties of nitracrine and amsacrine analogs.

For seven new methoxy and/or nitro derivatives of acridine antitumor drugs, nitracrine and amsacrine, biological activity in a few in vitro tests, as well as activity against experimental murine tumors Sarcoma-180 and Leukemia L1210 were investigated. Acute toxicity on mice (LD50) was also determined. High activity in vitro and specific activity against Sa-180 were found to be characteristic features of nitracrine, whereas amsacrine was characterized by high antileukemic activity. Methoxylation of position 2 of the acridine ring in both drugs suppressed their characteristic activity. Besides, substitution of the aminoalkyl side chain in nitracrine by methanesulfon-m-anisidine group suppressed its high antitumor activity, and the presence of a nitro group in position 1 of amsacrine suppressed its antileukemic activity. Comparison of biological properties of nitracrine, amsacrine and their analogs indicated differences in some steps of their mode of action.

Aminoacridines↗

PubMed1989

32P-post-labeling analysis of DNA adduct formation by antitumor drug nitracrine (Ledakrin) and other nitroacridines in different biological systems.

A 32P-post-labeling method has been employed to detect DNA adducts formed by derivatives of nitro-9-aminoacridine in both cellular and non-cellular systems. The treatment of HeLa S3 cells in culture or Ehrlich ascites tumor cells in vivo with nitracrine and two other antitumor 1-nitro-9-aminoacridines, denoted C-857 and C-1006, resulted in covalent binding of these compounds to cellular DNA. Each derivative studied gave rise to a distinct pattern of adduct spots and the similarity of the respective adduct profiles was noted for the both cellular models. Calf thymus DNA samples modified in vitro with nitracrine and C-857 in the presence of either rat hepatic microsomal fraction or dithiothreitol yielded chromatographic profiles resembling those obtained in the cellular systems, suggesting similarity in the DNA adduct structures. There were also neither qualitative nor quantitative differences in calf thymus DNA modification by these two 1-nitro derivatives between aerobic and anaerobic conditions, thus the reduction of a nitro group seems not to be the only determinant of covalent binding to DNA in vitro. No DNA adduct formation was detected in the cellular systems used with 2-nitro and 4-nitro isomers of nitracrine that are devoid of cytotoxic activity, which provides further evidence that both covalent binding and DNA crosslinking, but not intercalation, are responsible for cytotoxic and antitumor properties of 1-nitro-9-aminoacridines.

Aminoacridines↗

PubMed1989

DNA damage and cytotoxicity of nitracrine in cultured HeLa cells.

The effects of nitracrine (1-nitro-9-(3,3-N,N-dimethylaminopropylamino)acridine on DNA of cultured HeLa cells were studied. DNA strand breakage and interstrand cross-linking as well as DNA-protein cross-linking were measured by means of an alkaline elution technique and were compared with the cytotoxic effect of the drug. Interstrand cross-links were not detectable in the concentration range that inhibited cell growth up to 99%. DNA single-strand breaks were found when cells were treated with highly cytotoxic doses of the drug. DNA breakage was not reparable and exhibited a tendency to increase during incubation after drug removal. The only chromatin lesion induced by sublethal doses of nitracrine were DNA-protein cross-links which persisted for 24 h after drug treatment. It is concluded that DNA breaks represent degraded DNA from dying cells, whereas DNA-protein cross-links are specific cellular lesions, which may be responsible for the cell-killing effect of nitracrine.

Aminoacridines↗

PubMed2004

Cytotoxicity of nitroheterocyclic compounds, quinifuryl and nitracrine, towards leukaemic and normal cells on the dark and under illumination with visible light.

The cytotoxicity of two nitroheterocyclic compounds (NHCD), Nitracrine, 1-nitro-9(3-3-dimethylaminopropylamino) acridine and Quinifuryl, 2-(5'-nitro-2'-furanyl) ethenyl-4-[N-[4-(N,N-diethylamino)-1'-methylbutyl] carbamoyl] quinoline, towards two lines of leukaemic cells and a line of non-transformed cells, was measured in comparison, on the dark and under illumination with visible light (350-450 nm). Both drugs showed highly elevated cytotoxicity when illuminated with LC(50) values 7-35 times lower after 1 h illumination compared to 1 h incubation of cells incubation with drug on the dark. Cytotoxicity of Nitracrine toward all cell lines studied exceeded that of Quinifuryl, both on the dark and under illumination, so that approximately 10 times lower concentration of former drug was needed to reach the same toxicity as the latter. General toxic effect was calculated as a direct cell kill and a cell proliferation arrest. The effect >80% for both drugs was achieved after 1 h cell illumination with as low drug concentrations as 0.2 microM for Quinifuryl and 0.02 microM for Nitracrine.

Animals↗

PubMed1989

Hypoxia-selective antitumor agents. 1. Relationships between structure, redox properties and hypoxia-selective cytotoxicity for 4-substituted derivatives of nitracrine.

The nitroacridine derivative 9-[[3-(dimethylamino)propyl]amino]-1-nitroacridine (nitracrine) is selectively cytotoxic to hypoxic tumor cells in culture. However, the compound undergoes reductive metabolism too rapidly, with the reduction not being sufficiently inhibited by molecular oxygen in aerobic tissues, for it to demonstrate the same activity in vivo. In a search for derivatives with lower reduction potentials, we have synthesized and evaluated a series of derivatives bearing 4-substituents with a wide range of electronic properties. The one-electron reduction potentials (E(1] of these compounds, when compared under conditions of equivalent ionization, were highly correlated with sigma p values. However, at pH 7 the influence of substituent electronic properties was modified by prototrophic equilibria, with the basic nature of the acridine limiting the extent to which ring substituent electronic effects can be used to modulate reduction potential of the 1-nitro group. Nevertheless, comparison of the kinetics of the killing of AA8 cells under hypoxia suggests that some metabolic stabilization of the compounds can be achieved by the use of electron-donating substituents, with such compounds retaining the hypoxia-selective toxicity of nitracrine in cell culture. However, the 4-substituted nitracrines show no clear relationship between E(1) and cytotoxic potency, in distinct contrast to simpler nitroheterocycles such as nitroimidazoles.

Aminoacridines↗

PubMed1996

Hypoxia-selective antitumor agents. 13. Effects of acridine substitution on the hypoxia-selective cytotoxicity and metabolic reduction of the bis-bioreductive agent nitracrine N-oxide.

A series of nuclear-substituted derivatives of nitracrine N-oxide (2; a bis-bioreductive hypoxia-selective cytotoxin) were prepared and evaluated, seeking analogues of lower nitroacridine reduction potential. Disubstitution with Me or OMe groups at the 4- and 5-positions did not provide analogues with one-electron reduction potentials significantly lower than those of the corresponding monosubstituted derivatives (E(1) ca. -350 mV for both the 4-OMe and 4,5-diOMe compounds). This appears not to be due to a concomitant raising of the acridine pKa but to a lack of direct electronic effect of substituents in the ring not bearing the nitro group. Conversely, placing two OMe groups in the nitro-bearing ring does result in a substantial further lowering of reduction potential (the 2,4-diOMe analogue has an E(1) of -401 mV). The mono- and disubstituted N-oxides have substantially lower cytotoxicities than the parent nitracrine N-oxide 2 but generally retain very high hypoxic selectivity. The OMe-substituted N-oxides all showed greater metabolic stability than 2 in hypoxic AA8 cell cultures, and the 4-OMe compound 6 had improved activity in EMT6 multicellular spheroids suggesting that this metabolic stabilization may allow more efficient diffusion in tumor tissue. The parent compound 2 was selectively toxic to hypoxic cells in KHT tumors in vivo and clearly superior to nitracrine itself (although only at doses which would eventually be lethal to the host). The analogues of lower E(1), including 6, were not superior to 2 in vivo, indicating that metabolic stabilization of the nitro group is not alone sufficient to improve therapeutic utility.

Acridines↗

PubMedDate not supplied

In vitro binding of nitracrine to DNA in chromatin.

In the presence of sulfhydryl compounds nitracrine, an anticancer drug, binds covalently to DNA. The accessibility of DNA in chromatin both to nitracrine and to 8-methoxypsoralen, which was used as a reference compound in this study, when assayed in NaCl concentrations from 0 to 2 M show similar characteristics. The initial decrease reaches a minimum at 0.15 M NaCl above which dissociation of non-histone proteins and histones at higher ionic strengths is demonstrated by an increase in accessible sites. The relative accessibility of DNA in chromatin to nitracrine is, however, lower than that found for 8-methoxypsoralen. Partial dissociation of chromatin with 0.7 M NaCl increases the accessibility of DNA in chromatin when assayed in the absence of NaCl but has no apparent influence when estimated at ionic strength close to physiological conditions.

Aminoacridines↗

PubMed1999

Crosslinking of cellular DNA by nitracrine and furocoumarin derivatives.

The anticancer drug, nitracrine, a 1-nitro-9-aminoalkyl derivative of acridine exhibits potent cytotoxic effects which are due to its metabolic activation, followed by covalent binding to macromolecules--DNA being the target for the drug. The renaturable fraction of DNA from L-1210 cells pretreated with nitracrine is assayed by means of ethidium bromide fluorescence assay and chromatography on hydroxyapatite column. The effect of the drug was compared with furocoumarins of different DNA crosslinking potencies. The existence of crosslinks in DNA upon incubation of cells with nitracrine (1-4 microM) have been confirmed with two different methods under the conditions where 8-methoxypsoralen, a classic crosslinking agent induced the renaturation. The DNA preparation isolated from the drug pretreated cells exhibited decreased transcriptional template activity with E. coli DNA-dependent RNA polymerase.

Animals↗

PubMed1980

Effect of cyclophosphamide vinblastine and nitracrine on bioelectric properties of the frog skin epithelium in vitro.

The influence of cyclophosphamide, vinblastine and nitracrine on the membrane sodium transport was studied using the frog skin epithelium and short-circuit current technique. Profound changes of bioelectric parameters were observed. The final effects showed a statistically significant drug-concentration dependence. A considerably weaker response of vinblastine-pretreated and nitracrine-pretreated epithelia to vasopressin was also observed. Basing on these observations and some other data obtained by different techniques, it is suggested that these drugs influence the function of the cellular membrane while making it less permeable in the case of cyclophosphamide or vinblastine and more permeable in the case of nitracrine. Presumably this initial effect has something to do with the final cytostatic effect of the drugs.

Aminoacridines↗

PubMed1988

Mutagenic and clastogenic activity of nitracrine analogues in cultured V79 Chinese hamster cells.

Nitracrine is used clinically as an antitumour agent, and analogues are actively being developed in some laboratories. The mutagenic activity of 9-[(3-dimethylaminopropyl)amino]-acridine and its 1-nitro (nitracrine), 2-, 3- and 4-nitro derivatives was evaluated at the 6-thioguanine and ouabain resistance loci in cultured Chinese hamster fibroblasts (V79-171b cell line). The des-nitro, 2- and 3-nitro caused no statistically significant mutagenic activity at either locus. Each of these 3 compounds weakly increased (approximately 2-fold) the incidence of micronuclei in the same cell line when tested at cytotoxic doses. Both the 1- and 4-nitro compounds increased the incidence of 6-thioguanine resistant cells from around 1 in 10(-6) to approximately 1 in 10(-4). The former compound significantly increased the frequency of ouabain-resistant cells. Both of these compounds were potent inducers of micronuclei in V79-171b cells, indicating high clastogenic activity. It would appear prudent to regard both of these compounds as potential human carcinogens.

Aminoacridines↗