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PubMed1999

Phase I study of the cytotoxic agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA) is a new DNA-intercalating drug with a dual mode of cytotoxic action that is thought to involve topoisomerases I and II. On the basis of novelty of action and promising preclinical activity against solid tumours in mice, DACA was selected for clinical trial under the auspices of the Cancer Research Campaign, United Kingdom. We report the phase I findings of a 3-h infusion regimen, repeated 3-weekly, of escalating doses through 18-1000 mg/m2 given to 31 patients with solid malignancies. A maximum tolerated dose (MTD) of 750 mg/m2 was identified, with 3 of 6 cycles being abandoned at 1000 mg/m2. Dose-limiting toxicity took the form of infusional arm pain, in some cases associated with facial discomfort, that was of rapid onset and subsided quickly on the cessation of infusion. The mechanism is unclear but is modulated to some extent by the rate of drug delivery, and it was unaffected in this study by concurrent anti-inflammatory or opiate medication. No host or tumour anti-proliferative activity was observed at these doses, and only minimal toxicity of any other kind was evident. Animal data suggest that the MTD achieved with this schedule may be sub-therapeutic in humans. It is therefore important that efforts be continued to explore methods of giving higher doses of DACA.

Acridines↗
PubMed1999

Metabolism of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in cancer patients undergoing a phase I clinical trial.

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA) is an experimental antitumour agent that has just completed phase I clinical trials in New Zealand and the United Kingdom. Urine (0-72 h) was analysed from 20 patients receiving DACA infused over 3 h (dose range 60-1000 mg/m2, the latter being the highest dose achieved in the trial). Aliquots were analysed for DACA and its metabolites by high-performance liquid chromatography (HPLC). Over 72 h, 44+/-5% (range 20-60%) of the dose was recovered in the urine, with 0.8+/-0.3% (range 0-3.1%) occurring as DACA. The major urinary metabolite was DACA-N-oxide-9(10H)acridone, accounting for 34+/-3% of the dose. Minor metabolites were identified as N-monomethyl-DACA-9(10H)acridone (2.0+/-0.5%), DACA-9(10H)acridone (3.3+/-0.5%), N-monomethyl-DACA (0.2+/-0.1%) and DACA-N-oxide (0.5+/-0.1%). No ring-hydroxylated metabolite was detected. The urinary excretion of metabolites was greatest over 0-6 h in most patients. The composition of urinary metabolites was also independent of the delivered dose. Plasma was sampled at intervals throughout the infusion and at time points up to 48 h post-administration. The major plasma metabolites observed were DACA-9(10H)acridone and DACA-N-oxide-9(10H)acridone. These results indicate that, based on urinary excreted metabolites, the major biotransformation reactions for DACA in humans involve N-oxidation of the tertiary amine side chain and acridone formation, both of which appear to be detoxication reactions.

Acridines↗
PubMed1992

H+/glycyl-glycine cotransport in eel intestinal brush-border membrane vesicles: studies with the pH-sensitive dye Acridine orange.

Monitoring the fluorescence quenching of the pH-sensitive dye Acridine orange, proton accumulation in the presence of an inside-negative transmembrane potential was measured in eel (Anguilla anguilla) intestinal brush-border membrane vesicles. It was demonstrated that the proton accumulation was specifically increased by the presence of the dipeptide glycyl-glycine in the extravesicular space, showing saturation kinetics at increasing dipeptide concentrations and was specifically inhibited by diethylpyrocarbonate. Data reported suggest the presence of an electrical-potential-dependent H+/glycyl-glycine cotransport system in the eel intestinal brush-border membrane vesicles.

Acridine Orange↗
PubMed1979

Dimethyl-10,12-benz(a)acridine; evidence for differential effects on the synthesis of RNA of mammalian or avian fibroblasts and some RNA viruses.

We have studied the differential effect of dimethyl-10,12-benz(a)acridine (DBMAcr) on the synthesis of RNA of chicken or mouse fibroblasts in culture and that of some RNA-containing viruses such as Rous sarcoma virus and Mengovirus. DMBAcr at low concentrations blocks the cell multiplication of both normal and Rous sarcoma virus-transformed chicken fibroblasts in culture; it affects transformed cells more than normal ones. The cell growth inhibiting effect of DMBAcr is reversible after short periods of incubation. DMBAcr depresses the synthesis of cellular DNA and RNA in parallel. Concurrently the synthesis of protein proceedes at a relatively high rate in DMBAcr-treated cultures. Its inhibitory effect on cellular RNA synthesis is mostly due to a block in the formation of 28 S and 18 S ribosomal RNA species; in contrast, the synthesis of 45 S ribosomal RNA precursor is proceeding at almost control rate. Also, the synthesis of heterogeneous nuclear RNA is not blocked by DMBAcr. The production of Rous sarcoma virus in transformed fibroblasts is not affected by DMBAcr. Since this is correlated with persisting high rates of protein and heterogenous nuclear RNA synthesis, the effects of DMBAcr suggest that the synthesis of Rous sarcoma virus-RNA shares the specificity of messenger and heterogeneous nuclear RNA. DMBAcr inhibits the synthesis of viral RNA of Mengovirus under conditions where the synthesis of total cellular RNA is not appreciably depressed, suggesting its differential effect on the DNA-directed and the RNA-directed RNA synthesis.

Acridines↗
PubMed1982

Rat liver microsomal metabolites of 7-methylbenz[c]acridine.

The metabolism of the weak carcinogen 7-methylbenz[c]acridine (7MBAC) was examined in rat liver microsomes from 3-methylcholanthrene(MC)-induced animals by the use of mixed 14C- and 2H-labelled substrate. The three metabolites identified by spectroscopic and chromatographic examination were 7-OHMBAC and two dihydrodiols. The dihydrodiols were assigned structures consisted with attack on the 8,9- and 5,6- or K-region of the aromatic system.

Acridines↗
PubMed1992

Comparative metabolism of 7H-dibenzo[c,g]carbazole and dibenz[a,j]acridine by mouse and rat liver microsomes.

The comparative metabolism of the carcinogenic pollutants 7H-dibenzo[c,g]-carbazole (DBC) and dibenz[a,j]acridine (DBA) was investigated in vitro using 3-methylcholanthrene (3MC) induced Sprague-Dawley rat and Hsd:ICR(Br) mouse liver microsomal preparations with benzo[a]pyrene (BaP) as the positive control. Metabolites were isolated and separated by HPLC and identified by spectroscopic and co-chromatographic techniques using synthetic standards. The major metabolites of DBC were the phenols: the 5-OH-DBC, 3-OH-DBC, and 2-OH-DBC. Traces of 1-OH-DBC were also found yet no dihydrodiols were identified. The major metabolites of DBA were the 3,4-diol-DBA and 5,6-diol-DBA, 1,2-diol-DBA, DBA-5,6-oxide and 4-OH-DBA. Treatment of both mice and rats with 3MC resulted in significant (P less than or equal to 0.05) increases relative to control in the microsomal metabolism of DBA to dihydrodiol and phenol metabolites, similar to that observed for BaP. 3MC-induced rat liver microsomes significantly (P less than or equal to 0.05) increased DBC metabolism relative to control microsomes whereas DBC metabolism was not increased with 3MC-induced mouse liver microsomes. These data indicate that different enzymatic pathways are involved in the metabolic activation of DBC in the Hsd:ICR(Br) mouse and Sprague-Dawley rat.

Acridines↗
PubMed1995

32P-postlabelling analysis of dibenz[a,j]acridine-DNA adducts in mice: identification of proximate metabolites.

N-Heterocyclic polynuclear aromatics are widely-occurring environmental pollutants formed during the pyrolysis of nitrogen-containing organic chemicals. Dibenz[a,j]acridine (DBA), a member of this class, has been shown to be a skin carcinogen in mice. We undertook studies to determine the organ distribution of DBA-DNA adducts and to identify the DBA metabolites which lead to the formation of carcinogen-DNA adducts in vivo. DBA and its metabolites, trans-DBA-1,2-dihydrodiol (DBA-1,2-DHD) trans-DBA-3,4-dihydrodiol (DBA-3,4-DHD) and trans-DBA-5,6-dihydrodiol (DBA-5,6-DHD), were topically applied on mice. DNA was isolated using enzyme-solvent extraction methods, and analyzed for carcinogen-DNA adducts using 32P-postlabelling. In skin, DBA produced two distinct adducts (Adducts 1 and 2). The same two adducts were seen when DBA-3,4-DHD was applied. In addition, the total adduct level elicited by DBA-3,4-DHD was twice that of the parent compound. Two adducts (Adducts 3 and 4) were also seen in mouse skin when DBA-5,6-DHD was applied, but these differed chromatographically from adducts seen with DBA. However, when DBA-3,4-DHD was applied and analyzed using sensitive nuclease P1 32P-postlabelling, all four adducts could be detected. These results suggest that the major route of DBA activation to DNA-binding species in skin is through formation of DBA-3,4-DHD and subsequent metabolism of this compound to a bay-region diol-epoxide. However, we postulate that another activation pathway may proceed through a bis-dihydrodiol-epoxide.

Acridines↗
PubMed1994

Fluorescence spectroscopic studies on the identification and quantification of 7H-dibenzo[c,g]carbazole and dibenz[a,j]acridine metabolites.

Fluorescence spectroscopic techniques were developed and employed in the identification and quantitation of the metabolites of the carcinogenic pollutants 7H-dibenzo[c,g]carbazole (DBC) and dibenz[a,j]acridine (DBA) after HPLC separation. Metabolites formed in vitro with 3-methylcholanthrene (3-MC)-induced Sprague-Dawley rat liver microsomal preparations were used as the model for this research. The fluorescence spectra of the three major DBC metabolites matched those of the synthetic standards, 1-OH-, 3-OH- and 5-OH-DBC, respectively. Similarly, the fluorescence spectra of the four major DBA metabolites matched those of the synthetic standards, 1,2-diol-, 3,4-diol-, 5,6-diol- and 5,6-epoxide-DBA, respectively. Synchronous fluorescence spectroscopy (SFS) has been especially helpful for the identification of these metabolites since it produces a single peak for each compound. Regression equations of the SFS peak areas versus concentrations of the synthetic standards were used to calculate quantities of the microsomal metabolites from the SFS peak areas of the metabolites. These values were comparable with those quantities calculated from radioactivity measurements. The use of HPLC combined with SFS is a convenient and sensitive non-radiometric method which can be used to identify and quantify DBC and DBA metabolites.

Acridines↗
PubMed1991

Changes of DNA-acridine orange binding in monocytes and endothelial cells of hypertensive arteries.

The interactions of monocytes and endothelial cells were examined employing acridine orange (AO) binding to chromatin as an electron microscopic probe for studying changes in nuclear activity. The number of AO labeled nuclei were determined in adherent and sub-endothelial monocytes, and endothelial cells either associated with or devoid of monocytes in mesenteric arteries of renal hypertensive and normotensive rats. No AO-positive cell nuceli were found in the few adherent monocytes in the normotensive rats while in hypertensive rats 63% of the adherent monocytes and 86% of the subendothelial monocytes were labeled by AO. The number of AO-positive cell nuclei increased in the endothelium from 2% in normotensive rats to 17% in hypertensive animals. Fifty-seven percent of these endothelial cells were associated with monocytes adhering to their surfaces. Thirty-nine (52%) of AO-positive and 24 (52%) of AO-negative cell pairs represented 84% of cell pairs with identical nuclear activity. These findings indicate a sequential interaction of monocytes and adjacent endothelial cells recognized at the nuclear level. According to other experimental work the binding capacity of chromatin for AO increases as cell nuclei are reactivated by stimulation of cell proliferation. In addition, AO labeling of chromatin visualized electron microscopically is confined to three of the four stages of the cell cycle. Therefore AO labeling in the present experiments might indicate the reentrance of monocytes and endothelial cells into the cell cycle.

Acridine Orange↗
PubMed1983

Denaturation of RNA and DNA in situ induced by acridine orange.

The products of interaction of acridine orange (AO) with single-stranded (ss) nucleic acids are precipitates which exhibit red luminescence. Titration of rRNA or thymus DNA with AO results in formation of such products suggesting that the dye, per se, denatures double-stranded (ds) sections of these biopolymers. This transition, measured as the increase of red luminescence, a concomitant decrease of green fluorescence, and followed by an increase of light scatter of the AO-nucleic acid complexes, is cooperative and at 0.15 N NaCl occurs at 4-20 and 10-50 microM range of AO concentration for rRNA and DNA, respectively. The changes in stainability of nucleic acids in situ, in permealized cells, occur at higher AO concentration. Thus, the transition of RNA in situ is biphasic and seen at 20-120 microM AO. In the presence of EDTA, however, the change is monophasic and shifted to the 10-30 microM range of AO concentration. The change in stainability of DNA also shows two phases: one at 30-60 microM and another at 70-120 microM of AO. Extraction of basic proteins with 0.08 N HCl shifts the transition of DNA to the 30-60 microM AO concentration and makes it monophasic. The observed differences in denaturability of RNA vs DNA explain the specificity of AO in differential staining of these bipolymers in histochemical reactions. In living cells the products of interaction of AO with nucleic acids are detected by electron microscopy. In the cytoplasm of interphase cells the formation of dense precipitates within ribosomes and polysomes, simultaneous with a specific retraction of ribosome-polysome complexes from the periphery of the cell to the nucleus is evident. The latter suggests higher order organization of these particles involving their association with each other or with the nucleus via polyanionic macromolecules which collapse upon binding with AO. The DNA in heterochromatin is more sensitive to AO-induced denaturation, as evidenced by the fact that the dense complexes are formed preferentially in the regions of condensed chromatin of the interphase nucleus, or in metaphase chromosomes.

Acridine Orange↗
PubMed1990

Acridine orange-induced precipitation of mouse testicular sperm cell DNA reveals new patterns of chromatin structure.

Precipitate resulting from interaction between certain intercalators, such as acridine orange (AO), and nucleic acids can be detected by electron microscopy. Formation of precipitate in nuclei of live cells is modulated by chromatin structure. Susceptibility of in situ DNA to precipitation was studied in mouse testicular germ cells during various stages of sperm maturation. DNA in round spermatid chromatin, similar to somatic cell euchromatin, was rather resistant to precipitation; the electron-dense precipitate was granular and randomly distributed. DNA in elongated spermatids was more susceptible to precipitation; the products were in the form of fibers. At early stages of spermatid maturation these fibers were distributed uniformly throughout the entire nucleus. At later stages, the products appeared as approximately 25-nm-thick fibers arranged longitudinally in arrays within the nucleus. With further cell maturation, fibers in the anterior portion of the nucleus appeared to fuse, forming homogeneously dense product. These fibrous products likely represent AO interactions with DNA in chromatin in which transition proteins had replaced histones. Changing patterns of these precipitated fibers likely reflect progressive stages of chromatin condensation, which starts at the center and anterior portion of the nucleus where the fibers coalesce. Mature sperm cell DNA, known to be complexed with protamines, was more resistant to AO-induced precipitation. The data suggest that precipitation induced by AO and monitored by electron microscopy may be a useful probe of nuclear chromatin structure.

Acridine Orange↗
PubMed1991

Impossibility of acridine orange intercalation in nuclear DNA of the living cell.

The ability of a "vital" dye, acridine orange (AO), to intercalate into the DNA of living cells was investigated by quantitative intensified fluorescence microscopy and digital imaging under various conditions of dye concentration, excitation light intensity, and ionic concentration. Our results demonstrate that the bulk of chromatin DNA is packed in a way that does not allow AO intercalation. At low dye concentrations and very low levels of light intensity, the only fluorescent structures observed inside the nucleus are the nucleoli. This nonpermissive state of the chromatin appears to be a characteristic feature of the nucleus in living cells. AO intercalation into DNA can be mediated by raising the nuclear Na+ concentration. This was achieved here by using a cation carrier, monensin, a procedure which permits the avoidance of cell permeabilization. Furthermore, we show that the discharge of lysosomal enzymes in the living cell, via a targeted photodynamic reaction which occurs at high levels of light intensity, can also release the constraints which impede dye intercalation into nuclear DNA. In conclusion, studies carried out under conditions where intercalative dyes such as AO are able to stain the nuclear DNA have to be interpreted with caution and do not provide direct evidence on the structural state of native chromatin. The molecular origin of the absence of AO intercalation in chromatin of the living cell is discussed with regard to the restrained uncoiling of the double helix which is required for dye intercalation.

Acridine Orange↗
PubMed1990

Specific interaction of the new fluorescent dye 10-N-nonyl acridine orange with inner mitochondrial membrane. A lipid-mediated inhibition of oxidative phosphorylation.

The fluorescent dye 10-N-nonyl acridine orange (NAO), known as specifically associated with mitochondria, has been reported to have a cytotoxic effect when high doses were applied to cells. Presently, the biochemical basis of its toxicity was investigated on isolated rat liver mitochondria. At low concentrations, NAO strongly inhibited state 3 respiration and ATP synthesis. At high concentrations, electron transport, ATP hydrolysis, Pi-transport and adenine nucleotide activities were also decreased. All these inhibitions can be explained by probe-cardiolipin interactions which could induce the collapse of energy conversion and/or the modification of membrane fluidity.

Acridine Orange↗
PubMed1995

Kinetic studies on the formation of acridine-linked DNA triple helices.

We have used DNase I footprinting to measure the rate of intermolecular triple helix formation at the target sites A6G6.C6T6 and G6A6.T6C6 with the acridine-linked oligonucleotides Acr-T5C5 and Acr-C5T5, respectively. Under pseudo first-order reaction conditions we find that the reactions are slow, with half-lives of several minutes. The rates are dependent on the concentration of the third strand oligonucleotide and yield bimolecular association rate constants of 300 M-1.s-1 for Acr-T5C5 binding to A6G6.C6T6 and 2000 M-1.s-1 for the interaction of Acr-C5T5 with G6A6.T6C6.

Acridines↗
PubMed1976

Acridine orange fluorescence cytochemistry for detecting lymphocyte immunoreactivity.

Acridine orange staining reveals changes within 3 hours of in vitro stimulation of normal rat lymphocytes with mitogens, and of immune rat lymphocytes with the sensitizing antigen. An increased number of red fluorescent cytoplasmic organelles, presumably lysosomes are seen by fluorescence microscopy. Fluorimetry of the supernatants from stained cell suspensions suggests an overall decreased cell uptake of the dye. The microscopy and fluorimetry detected early events in the reaction of lymphocytes from tumour-bearing rats with the target tumour cells. It would appear that the changes in intracellular behaviour of the dye and in overall cell uptake after immune stimulation are a reflection of dissociated variations in internal and external cell membrane permeability, and may provide simple general means for recognizing cellular immune reactions.

Acridines↗
PubMed1979

Photodynamic effects of dyes on bacteria. III. Mutagenesis by acridine orange and 500-nm monochromatic light in strains of Escherichia coli that differ in repair capability.

In the presence of acridine orange (AO) and monochromatic 500-nm light, the recombination-deficient strain of Escherichia coli, WP10 (recA), showed a 15-fold increase in mutation rate over the wild-type (WP2) strain. Under the same conditions, strain Bs--1 (uvrB lexA lon) showed a 5-fold increase in mutation rate over strain WP2. In contrast, the endonuclease-deficient, strain, WP2s (uvrA), showed a lower AO-500 nm mutation rate than wild-type. The extremely high mutation rate of the recA strain cannot be due to error-prone inducible SOS repair since the inducible recA + function is absent. Repair of the AO-500 nm-induced lesions is likely due to a recA+-dependent, error-free, recombination process. It is concluded that the high mutation rates with AO-500 nm light obtained in chemostat cultures of recA and lexA strains occur as a consequence of errors during semi-conservative DNA replication in the presence of unrepaired DNA lesions.

Acridine Orange↗
PubMed1981

Azido analogs of acridine: photoaffinity probes for frameshift mutagenesis in Salmonella typhimurium.

In order to identify a photoaffinity probe for 9-aminoacridine frameshift mutagenesis, 20 azido analogs of acridine were synthesized and tested in Ames' Salmonella tester strains, TA1535, TA1537, TA1538 and their corresponding excision-repair-coefficient strains TA1975, TA1977 and TA1978, to determine their mutagenicity and toxicity relative to 9-aminoacridine. The substituent-mutagenicity patterns observed for these compounds agree very well with those obtained previously for non-azidoacridines. The results presented here show that the 2-azido-analog of 9-aminoacridine demonstrates biological activity similar to 9-aminoacridine prior to photolytic activation. With light activation, however, the 9-amino-2-azido derivative becomes more effective at producing frameshift mutations characteristic of 9-aminoacridine. Furthermore, this photolytic enhancement of mutagenesis appears to be due to the repairable lesion suggesting that covalent attachment of the drug occurs.

Acridines↗
PubMed1982

Photodynamic effects of dyes on bacteria. V. Mutagenesis by acridine orange and 460-nm or 500-nm light in strains of Escherichia coli that differ in repair capability.

With acridine orange (AO) and monochromatic 460-nm light, the mutation rate of the wild-type strain of Escherichia coli (WP2) was 3-fold higher than that of the endonuclease-deficient strain WP2 (uvrA). In addition, the mutation rates of the recombination-deficient strains WP10 (recA) and Bs-1 (uvrB lexA) were also about 3-fold less than that of wild-type strain. This observation is in striking contrast to the earlier results with AO and 500-nm light in which strains WP10 and Bs-1 yielded mutation rates that were 12-fold and 5-fold greater, respectively, than the wild-type response. The relatively large decrease in mutation rate when the uvrA endonuclease was absent together with structural considerations in the binding of AO to DNA lead us to propose that the major lesions leading to mutations produced by 460-nm light in the presence of AO may be true DNa single-strand breaks and occur before DNA replication.

Acridine Orange↗