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PubMed1990

The induction and repair of DNA damage detected by the DNA precipitation assay in Chinese hamster ovary cells treated with acridine orange + visible light.

The photodynamic effect of the dye acridine orange (AO) in combination with visible light (400-700 nm) was studied in Chinese hamster ovary (CHO) cells, the endpoints investigated being induction, as well as repair, of DNA strand breaks. Cells were treated for 20 min with AO (0.1-3.0 micrograms/ml), washed free of excess dye and subsequently exposed to low doses of visible light (2 x 40 W/8 W/m2) for 5-15 min. AO proved to be an efficient sensitizer for light-induced DNA strand breaks, detected with the DNA precipitation assay, and expressed as percentage of DNA precipitated. The induction of breaks was linear up to 0.5 micrograms/ml AO + 10 min of light, which corresponds to 55% precipitated DNA, and was dependent on the concentration of AO as well as on the dose of light delivered. As a comparison, 18 Gy of X-rays was required to yield an equivalent amount of induced DNA strand breaks. The rejoining of the light-induced DNA strand breaks was studied by incubating the AO-sensitized cells for 30-120 min at 37 degrees C directly after light exposure. A fast recover of 67-91% of the damage (compared to initial damage, recovery time = 0, and dependent on the concentration of AO) was observed during the first 30 min of incubation. However, a significant amount of DNA damage remained after 2 h of recovery. These remaining, long-lived lesions might be involved in the photoinduced and acridine-sensitized chromosomal aberrations and sister-chromatid exchanges (SCE). The significance of these observations is discussed in relation to AO-sensitized and photoinduced DNA damage and chromosomal alterations.

Acridine Orange↗
PubMed2006

Amino- and glycoconjugates of pyrido[4,3,2-kl]acridine. Synthesis, antitumor activity, and DNA binding.

A series of amino- and glycoconjugates of pyrido[4,3,2-kl]acridine and pyrido[4,3,2-kl]acridin-4-one have been prepared. The most active molecules, the amino conjugates 7 and 11, display a cytostatic activity against HT-29 cancer cells at micromolar concentration. This activity correlates well with a strong DNA binding. The molecules, amino or glycoconjugates, bind DNA by intercalation, the amino or glyco substituent being located in one groove. None of the molecules inhibits topoisomerase activity.

Acridines↗
PubMed2005

A non-crosslinking platinum-acridine hybrid agent shows enhanced cytotoxicity compared to clinical BCNU and cisplatin in glioblastoma cells.

Using clonogenic survival assays, we demonstrated that a new platinum-acridine hybrid agent, PT-ACRAMTU, is cytotoxic in SNB19 and U87MG glioblastoma cells at low-micromolar concentrations. PT-ACRAMTU is more cytotoxic than ACRAMTU (the platinum-free acridine), acts in a time and dose dependent manner, and appears to generate an apoptotic response in both cell lines on the basis of increased caspase-3 activity.

Acridines↗
PubMed2006

Analysis of cycloheximide-induced apoptosis in human leukocytes: fluorescence microscopy using annexin V/propidium iodide versus acridin orange/ethidium bromide.

Apoptosis is a highly regulated and programmed cell breakdown process characterized by numerous changes. Since it is implicated in many pathological as well as physiological processes, it is vital to have reliable methods for detecting cell death. In this study, we compared several methods for detecting apoptosis and necrosis in human leukocytes. Apoptosis was induced either by incubating the cells with various doses of cycloheximide (CHX) or by 312 nm UVB irradiation. The methods used for detecting apoptosis were light microscopy (May Grunwald-Giemsa and trypan blue staining), fluorescence microscopy (acridin orange/ethidium bromide and annexin V/propidium iodide staining) and agarose gel electrophoresis of fragmented genomic DNA. Our study showed that CHX-induced apoptosis in cultured peripheral blood mononuclear cells but had no effect on apoptosis in polymorphonuclear cells, so its effect depends on cell type. Evaluation and comparison of the methods for detecting apoptosis showed the following. A Giemsa-stained cytospin allows the main morphological characteristics of necrotic and apoptotic death to be recognized. Trypan blue staining, widely used for estimating cell viability, is valueless for detecting apoptosis. Both fluorescence methods provided reliable and reproducible results and distinguished clearly between subpopulations of apoptotic cells, and were closely intercorrelated. Although applicable to a wide spectrum of cell types, agar electrophoresis of extracted DNA cannot be applied to all cell types and apoptotic conditions. Generally, microscopic examination of acridin orange/ethidium bromide stained cells can be recommended as the most reliable of the methods tested.

Acridine Orange↗
PubMed2005

Acridine orange leukocyte cytospin test for central venous catheter--related bloodstream infection: a pediatric experience.

The aim of this study was to evaluate the acridine orange leukocyte cytospin (AOLC) test for the rapid diagnosis of septicemia caused by central venous catheters (CVCs), without removing the catheter, in a pediatric intensive care unit population. Twenty-six patients admitted in the pediatric intensive care unit of Azienda Ospedaliera "Ospedali Riuniti di Bergamo", Italy, were prospectively evaluated for CVC-related infection. Blood for culture was taken from all patients. Quantitative endoluminal cultures of the removed catheter tip by Cleri's technique and semiquantitative superficial cultures of the hub were performed. Gram staining and an AOLC smear were done according to Kite's technique. Four Staphylococcus CVC-related bloodstream infections were identified. CVC colonization was detected in 8 patients. Four had septicemia (Enterococcus faecalis, Escherichia coli, Klebsiella oxytoca, Candida glabrata) without CVC involvement. However, Gram staining and the AOLC test were negative in all cases. We conclude that cytocentrifugation and acridine orange staining of blood withdrawn by Kite's method from an in situ catheter, although simple, quick, and inexpensive, did not aid diagnosis in this pediatric population.

Acridine Orange↗
PubMed2005

Synthesis of acridine-nuclear localization signal (NLS) conjugates and evaluation of their impact on lipoplex and polyplex-based transfection.

We report on the synthesis of various acridine (Acr)-spacer-nuclear localization signal (NLS) peptide conjugates and explore whether their use as NLS-labeling agent of plasmidic DNA could improve gene nuclear import and expression into cells when mediated by synthetic DNA complexes. As the conditions of successful use of the NLS properties to enhance gene transfer are not clear, and with the aim of detecting and defining the requirements of NLS-enhanced transfection, we investigated gene delivery and expression into various cell lines with various DNA complexes (lipoplexes or polyplexes) that were formulated for various N/P ratios from various preformed Acr-spacer-NLS/DNA complexes (1:1, 5:1 and 10:1 molar ratio). For the in vitro transfection assays, the lipoplexes and polyplexes were formulated from the preformed Acr-spacer-NLS/DNA complexes and dioctadecylamidoglycylspermine (DOGS)/dioleylphosphatidylethanolamine (DOPE) 1:1 mol and branched polyethyleneimine (PEI) 25 kDa, respectively, which are very efficient in vitro gene transfer systems. We show by fluorescence experiments that part of the acridine-NLS-conjugates remains intercalated within the plasmid for most of the N/P lipoplexes and polyplexes investigated. We show that, as several other studies performed with NLS-conjugates that are not covalently linked to DNA, the expression of the transgene is in most cases not improved upon complexation of plasmidic DNA with NLS-intercalating conjugates prior to its formulation as lipoplexes or polyplexes.

Acridines↗
PubMed2006

Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents.

Transmissible spongiform encephalopathies (TSEs) are thought to arise from aggregation of a protease resistant protein denoted PrP(Sc), which is a misfolded isoform of the normal cellular prion protein PrP(C). Using virtual high-throughput screening we have selected structures analogous to acridine, 2-methyquinoline and 2-phenylquinazoline as potential therapeutic candidates for the treatment of TSEs. From the synthesis and screening of constructed libraries we have shown that an electron-rich aromatic ring attached through an amine linker to the position para to the ring nitrogen is beneficial to both binding to PrP(C) and the suppression of PrP(Sc) accumulation for acridine and 2-methylquinoline analogues. 2-Phenylquinazoline analogues appear to utilise a different mode of action by binding at a different location and/or pose. We report IC50s in the nanomolar range.

Acridines↗
PubMed2006

Determination of the binding affinities of plasmid DNA using fluorescent intercalators possessing an acridine skeleton.

Novel acridine derivatives, wherein the steric factor has been varied systematically through substitution at the 9 position of the acridine ring, were evaluated as convenient fluorescent probes for nucleic acid detection. The binding affinities of N-(9-acridinylthiocarbamoyl)amino acids (ATA) with plasmid DNA (pUC 19) were investigated using UV-vis spectrophotometry, fluorometric titration and quantum chemical calculations (AM1). From spectrofluorometric analysis, the binding constants for the DNA-ATA complexes were determined. To elucidate its DNA intercalation, the most preferable tautomeric structure of ATA was established by means of AM1 calculations.

Acridines↗
PubMed2004

Effect of a conjugated acridine moiety on the binding and reactivity of Cu(II)[9-acridinylmethyl-1,4,7-triazacyclononane] with DNA.

The DNA binding orientation and dynamic behavior of Cu(II) complexes of 1,4,7-triazacyclononane ([9]aneN(3)), 1, and an acridine conjugate, 2, were investigated by DNA fiber EPR (EPR=electron paramagnetic resonance) spectroscopy. Crystal and molecular structure of 2 were determined by X-ray diffraction. It has been shown that 1 binds to DNA in two different modes at room temperature; one species is rapidly rotating and the other is immobilized randomly on the DNA. The introduction of acridine to [9]aneN(3) fixed the [Cu([9]aneN(3))](2+) moiety of 2 in two different environments on the DNA: the g(mid R:mid R:) axis of one species (g( parallel)=2.26) is aligned perpendicularly to the DNA fiber axis whereas that of the other (g( parallel)=2.24) aligns<90 degrees with the DNA fiber axis. The different DNA binding structures of 1 and 2 are reflected also in their different efficiencies of DNA cleavage; 2 was found to be more effective both in oxidative and hydrolytic cleavage reactions.

Acridines↗
PubMed2004

Fluorescence of acridinic dyes in anionic surfactant solution.

The interaction of the cationic dyes acridine, 9-aminoacridine (9AA), and proflavine, with sodium dodecyl sulfate (SDS) was studied by electronic absorption, steady-state and time-resolved fluorescence spectroscopies. The dyes interact with SDS in the pre-micellar region leading in two cases to dimerization in dye-surfactant aggregates, but with distinct molecular arrangements. For proflavine, the observed red shift of the electronic absorption band indicates the presence of J-aggregate, which are nonfluorescent. In the case of 9AA, the aggregates were characterized as nonspecific (neither J- nor H-type is spectroscopically observed). The time-resolved emission spectra gives evidences of the presence of weakly bound dimers by the recovery of three defined decay times by global analysis: dye monomer (tau1 = 16.4 ns), dimer (tau2 = 7.1 ns), and a faster component (tau3 = 2.1 ns) ascribed to intracluster energy migration between monomer and dimer. Acridine has a weak interaction with SDS forming only an ion pair without further self-aggregation of the dye.

Acridines↗
PubMed2005

Determination of dipole moment in the ground and excited state by experimental and theoretical methods of N-nonyl acridine orange.

The absorption and fluorescence spectra of N-nonyl acridine orange are determined at room temperature (298 K) in cyclohexane, benzene, carbon tetrachloride, chloroform, chlorobenzene and dichloromethane. The ground state of dipole moment was obtained by impedance measurements using Guggenheim-Debeye's method. The experimental excited state dipole moment of N-nonyl acridine orange was determined using Bakhshiev's and Kawski-Chamma-Viallet's formulae and solvent polarity parameter proposed by Reichardt. These experimental results were completed with theoretical results using quantum chemical methods. The experimental (muexp=10.76 D) and theoretical (mucal=9.9 D) dipole moments in the ground and excited state (muexp*=14.56 D) were compared.

Acridine Orange↗
PubMed1969

Mechanisms of inhibition of pyrimidine dimer formation in deoxyribonucleic acid by acridine dyes.

The ultraviolet (UV)-induced formation of cyclobutyl pyrimidine dimers in Escherichia coli deoxyribonucleic acid (DNA) in vitro has been investigated in terms of the mechanism of inhibition by acridine dyes, the effect on dimer yield of specific singlet and triplet quenchers, and the mechanism of dimer formation. Our results indicate that (a) energy transfer is important in dimer reduction by acridines, (b) this transfer occurs from the singlet (S(1)) of DNA, and (c) at room temperature triplet quenchers do not reduce dimer yield in DNA.

Acetone↗
PubMedDate not supplied

Synthesis and cytotoxic evaluation of N1,Nm-bis[(tetrahydrobenzo[a]acridin-12-yl)phenyl]alkanediamides and N1,Nm-bi.

The title compounds were synthesized in four steps from 5,5-dimethyl-1, 3-cyclohexanedione as starting material. These compounds were evaluated against 60 tumoral cell lines, whereas the N1,Nm-bis[benzo[c]acridin-7-yl]phenyl]alkanediamides displaying significant cytotoxic activity, the corresponding N1,Nm-bis[benzo[a]acridin-12-yl]phenyl]alkanediamides derivatives were found to be less cytotoxic.

Acridines↗
PubMed1996

The relationship between acridine orange fluorescence of sperm nuclei and the fertilizing ability of human sperm.

OBJECTIVE: To determine whether the outcome of IVF can be predicted by acridine orange (AO) nuclear fluorescence of sperm. DESIGN: Based on the fact that AO nuclear fluorescence color after acid treatment reflects maturity (green fluorescence) or immaturity (yellow to red fluorescence) of spermatozoa, the relationships between sperm maturity and the outcome of IVF, subzonal insemination, or intracytoplasmic sperm injection (ICSI) were investigated. SETTING: The IVF program at the Obstetrics and Gynecology Hospital, Fukushima Medical College. PATIENTS: Sixty-eight patients undergoing 68 IVF treatment cycles. MAIN OUTCOME MEASURES: Acridine orange fluorescence of sperm nuclei and successful oocyte fertilization. RESULTS: conventional semen parameters (sperm concentration and percentages of motile or morphologically normal spermatozoa in semen) did not correlate with the incidence of spermatozoa with green AO fluorescent (mature) nuclei. When > or = 50% of spermatozoa in semen samples exhibited green AO nuclear fluorescence, IVF was always successful. When green AO nuclear fluorescence was < 50%, only 39% of IVF treatment cycles (13/33) were successful. Only green AO fluorescent spermatozoa were able to bind efficiently human zona pellucida. When the incidence of green AO fluorescent spermatozoa was < 50%, no pregnancy resulted even though an average of 26% of the oocytes could be fertilized by ICSI. CONCLUSIONS: The spermatozoa which fertilized oocytes in vivo and in IVF were limited to those whose nuclei exhibited green AO fluorescence. Intracytoplasmic sperm injection may be the method of choice when the incidence of green AO nuclear fluorescence is low regardless of the results of semen analysis.

Acridine Orange↗
PubMed1998

An automated new technique for scoring the rodent micronucleus assay: computerized image analysis of acridine orange supravitally stained peripheral blood cells.

We developed an automated image analysis system to obtain objective data for the rodent peripheral blood micronucleus assay with acridine orange (AO) supravital staining. The system was able to identify micronucleated reticulocytes (MNRETs) and to evaluate inhibition of bone marrow cell proliferation by measuring the reticular area of reticulocytes (RETs). We also developed automated equipment to produce homogeneous acridine orange-coated glass slides. This study was designed to compare automated scoring with manual scoring using 4 model clastogens and 2 mouse strains. The MNRET incidence induced by each clastogen was similar for automated and manual scoring, and there was good correlation (r=0.92) between the methods. In addition, an index of bone marrow toxicity based on the reticular area of RETs was compared to the conventional index (% of polychromatic erythrocytes (PCE) to total erythrocytes; PCE ratio) and was similar. The results indicated that our technique for computer-assisted image analysis for the micronucleus assay with AO supravitally stained peripheral blood RETs was comparable to conventional microscopic scoring, and it was superior in objectivity and statistical power.

Acridine Orange↗
PubMedDate not supplied

Direct acridine orange fluorescence examination of blood slides compared to current techniques for malaria diagnosis.

The renewed interest in the use of fluorochromes for malaria diagnosis prompted us to evaluate the acridine orange fluorescence technique on blood slides, and to compare it with established techniques using thick and thin blood films and the QBC malaria test, using the Giemsa-stained thick film technique as our standard method for comparison. We compared 123 positively diagnosed cases and 120 negative cases. For primary samples (day 0), the sensitivity of the thin blood film fluorescence acridine orange technique (AO) was 96.4%, and its specificity was 95.1%. In cases of imported malaria, with a prevalence rate of 16.2%, the positive predictive value was 79.2% and the negative predictive value 99.3%. Sensitivity of AO was significantly higher than that of Giemsa-stained thin blood films for parasitaemias < 5000/microL. The potential of AO for species diagnosis of Plasmodium was 85.2%, using Giemsa-stained thin films as the reference technique. Where QBC imposes a cost limitation, especially in developing countries, despite its high performance, the AO diagnostic technique is a valuable alternative, because of its simplicity, almost negligible cost, and its diagnostic reliability. The method may also have potential value in the diagnosis of other microbiological diseases.

Acridine Orange↗
PubMed1985

The activation and DNA binding of 7-methylbenz[c]-acridine catalysed by mouse liver microsomes.

The metabolism of the carcinogen, 7-methylbenz[c]acridine (7MBAC), in liver microsomes prepared from untreated, and phenobarbital sodium (PB) and 3-methylcholanthrene (MC) induced male C57BL/6 mice was examined by high pressure liquid chromatography (HPLC). The abilities of control and MC induced liver microsomes to catalyse covalent binding of the carcinogen to DNA were comparable (60 pmol 7MBAC bound/mg DNA), although this maximum binding level observed was achieved at different 7MBAC concentrations for control (100 microM) and MC induced (25 microM) preparations. In vivo binding of 7MBAC to liver DNA was greater than that observed for lung DNA of the same animals but over 21 h bound 7MBAC levels decreased to a greater extent in liver than in lung. One fraction of a digest of in vitro alkylated DNA gave a fluorescence emission spectrum very similar to that of 7-methyl-1,2,3,4-tetrahydrobenz[c]acridine. This result suggests that diol epoxides functionalised at the 1,2,3,4-positions may be ultimate carcinogens derived from 7MBAC.

Acridines↗
PubMed1990

Quantitation of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in plasma by high-performance liquid chromatography.

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide is a new experimental antitumour agent which has excellent in vivo activity against the Lewis lung tumour in mice. A reversed-phase high-performance liquid chromatographic method is described for the measurement of this agent in plasma. The internal standard was N-[2-(diethylamino)ethyl]acridine-4-carboxamide. The compounds of interest were extracted from plasma (0.2 ml) with acetonitrile and further purified on C18 solid-phase extraction Bond Elut columns. After elution with acetonitrile-ammonium acetate buffer and evaporation, the final separation was carried out on a C18 muBondapak column with fluorimetric detection. Over the plasma concentration range 100-5000 nM, the intra- and inter-assay coefficients of variation were less than 4.1 and 7.7%, respectively. The accuracy of the method varied from 97 to 105% of the theoretical values. The lowest concentration which could be measured with acceptable accuracy (+/- 10%) and precision (coefficient of variation less than 10%) was 10 nM. The method was sufficiently sensitive to allow pharmacokinetic analyses of 30 mumol/kg doses for more than six half-lives (t1/2) in rabbits (t1/2 = 4) and mice (t1/2 = 1.3 h).

Acridines↗