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The influence of acridine orange and THA on the growth of Mycobacterium tuberculosis H37Rv strain in 7H12 Middlebrook liquid medium was studied. As compared to acridine orange, THA also inhibited the growth of the H37Rv Mycobacterium tuberculosis strain but at much higher concentrations.
The antitumor effect against experimental tumors in mice of three acridine derivatives analog or homolog of N-[4'-(9-acridinylamino)-3'-methoxyphenyl]-methanesulfonamide has been investigated. The 3,6-bis-dimethylamino analog (DAMSA) showed important antitumor effect in murine leukemias and moderate effect in a solid tumor, the M5076 reticulosarcoma. The body weight loss of the treated mice was always within an acceptable range when 100 mg/kg were administered under the conditions of the experiment. However, a systemic toxic effect could be observed when 200 mg/kg were used. This preliminary data may be considered as an important step in the development of new acridine analogs with a different spectrum of antitumor activity.
The present study included 150 newborns; 100 clinically septic and 50 clinically aseptic who served as control. Out of 100 clinically septic newborns, blood culture was positive in 33 (33%), serum CRP was positive in 64 (64%) and acridine orange stained buffy coat smear was positive in 76 (76%). Serum CRP was found to be the most specific (specificity 96%) and acridine orange stained buffy coat smear examination the most sensitive (sensitivity 94.3%) test for diagnosis of neonatal septicemia.
Antitumor drugs from many chemical classes have been shown to induce protein-linked DNA breaks in cultured mammalian cells and in vitro in the presence of purified mammalian DNA topoisomerase II. The possibility that mammalian DNA topoisomerase II is an intracellular target which mediates drug-induced DNA breaks is supported by the following studies using 4'-(9-acridinylamino)methane-sulfon-m-anisidide (m-AMSA): (a) a single m-AMSA-dependent DNA cleavage activity copurified with calf thymus DNA topoisomerase II activity at all chromatographic steps of the enzyme purification; (b) m-AMSA-induced DNA cleavage by this purified activity resulted in the covalent attachment of protein to the 5'-ends of the DNA via a tyrosyl phosphate bond. This covalently linked protein has the same reduced molecular weight as purified calf thymus DNA topoisomerase II. The possibility that topoisomerase II-mediated DNA breaks may be responsible for cytotoxicity has also been investigated using a number of m-AMSA-related acridines. The level of topoisomerase II-mediated DNA breaks in vitro strongly correlates with the level of protein-linked DNA breaks in cultured cells and drug-induced cytotoxicity. These results suggest that mammalian DNA topoisomerase II may be a cytotoxic target of antitumor acridines.
The interaction of serotonin and acridine orange dye with DNA isolated from bacterium Escherichia coli and the yeast Candida utilis has been analysed by spectrofluorimetric method. Using data on competitive binding to DNA of serotonin and acridine orange, known as DNA intercalator, a conclusion concerning the formation of intercalated complex between serotonin and DNA has been made. It is shown that for yeast DNA the constant of intercalated binding of serotonin is 3,5-fold smaller than for the bacterial one.
Investigations have suggested that a correlation exists between DNA ploidy levels and prognosis in human breast carcinoma. Nuclear DNA content can be studied by flow cytometry or cytophotometric analysis. While both methods yield comparable results for DNA distribution, cytophotometry has the advantage of permitting both quantitative cell measurements and cytomorphologic identification of tumor cells. Microfluorimetric analysis of nuclear DNA content was carried out on acridine-orange-stained imprint smears of malignant breast tumors, with the DNA values plotted as a histogram distribution. Quantitative fluorescence measurements of breast carcinoma cells using the acridine-orange stain appeared to be a fairly rapid and simple method for DNA determination as compared to Feulgen DNA analysis. Following cytometric measurements, imprint smears were counterstained by the Giemsa stain and examined by cytomorphologic criteria. With the Giemsa counterstain, the same cytologic preparation could be studied both by quantitative cell measurements and by conventional cytomorphologic criteria. Results are illustrated, and possible implications of the use of this method in the study of tumor behavior and the diagnosis by cytologic methods are discussed.
The need for a technique that is more sensitive than the use of Romanowsky-stained thick blood films for detecting malaria parasites at low concentration in the blood is well recognized. One of the more promising methods appeared to be fluorochrome staining with acridine orange. However, reports on the efficacy of the technique were contradictory and it was not clear to what extent blood films taken under survey conditions would contain fluorescing artefacts that might confuse diagnosis. An investigation indicated that, provided reasonable care was taken, blood films made under survey conditions contained few confusing artefacts. However, it was found that, while acridine orange staining might have a slight advantage when large malaria parasites were present, it was inferior to routine Romanowsky staining for the detection of young trophozoites, the inferiority becoming more pronounced as the parasite concentration decreased.
Using the ability of lysosome-like alpha-granules of thrombocytes to accumulate flurochrome acridine orange, their transformation kinetics was studied in the course of cell viscous metamorphosis utilizing the fluorometric technique. It turned out that during the thrombin induced cellular viscous metamorphosis lysosomes released their contents: the process is stimulated by the presence of extracellular Ca2+. Competitive relations were revealed between the accumulation within cytoplasmic granules of thrombocytes of acridine orange and serotonin, and that of histamine and novocaine. The process of fluorochrome accumulation was found to be temperature dependent and to be inhibited by monoiodacetate.
The purpose of this work was to study the action of acridine orange and mitomycin C on the production of mutants of Streptomyces hygroscopicus, strain 0681. The mutagen activity of mitomycin C was shown to be high. The vegetative culture grown for 24 hours produced more mutants under the action of mitomycin C than spores did. Both acridine orange and mitomycin C caused the production of mutants in strain 0681. The morphology of colonies in these mutants was modified, the synthesis of hygromycin B was completely or partly blocked, and the composition of fatty acids changed quantitatively and qualitatively. Mutants induced by mitomycin C were highly active in the production of the complex of hygrolytin proteolytic enzymes.
It has been shown that the ratio between the intensity of luminescence band in the red spectrum region (640 nm) and that in the green one (530 nm) of acridine orange fluorochromed cells fixed under certain conditions alpha=I640/I530 is a specific character. The latter can be used for automatic classification of bone marrow cells and perypheric blood and for diagnostics of some pathological states of the cell. It has been found that the type of the changes of the ratio of alpha=I640/I530 at photochemical bleaching of fluorochromed cells under irradiation (436 nm) depends on the level of cell differentiation. Completely differentiated mature cells are characterized by a simultaneous decrease of luminescence intensity, both in the red (640 nm) and green (530 nm) spectrum regions. In undifferentiated cells (especially at the blast stage) a decrease of luminescence intensity in the red region (640 nm) is accompanied by an increase of the luminescence intensity in the green region (530 nm) which may serve as an additional specific character. The descovere effect of photobleaching of undifferentiated cells is suggested to be due to the photodestruction of dimers of acridine orange bound with monohelical regions of DNA.
250 MHz 1H N.M.R. spectra of a set of 9-substituted derivatives of acridine as solutes in DMSO-d6 were studied. Because of ABCD coupling figures, magnetic parameters were determined by means of simulated spectra. Semi-empirical correlations were proposed for chemical shifts. Moreover, pi distribution in the heterocycle was investigated. Results are discussed in relation to some weak biological properties of the acridine drugs.
To determine the relationship between sperm deoxyribonucleic acid (DNA) normality and fertilizing potential, 93 semen samples from 48 fertile donors and 45 male partners of infertile couples whose major abnormalities in the female partner had been ruled out were studied. Semen samples were assessed for conventional parameters (volume, percentage of normal morphology, percentage of progressive motility, sperm concentration, and round cell concentration) according to World Health Organization (WHO) guideline and acridine orange staining. The mean sperm concentration, percentages of progressive motility, and percentage of green fluorescing sperm in semen were significantly higher in samples from fertile donors (p < 0.005). When the parameters of semen quality were considered normal according to the standard WHO criteria, the mean percentages of green-fluorescing sperm were significantly higher in fertile donors than infertile patients (65.6% vs 53.3%; p < 0.05). Therefore, the acridine orange staining technique for evaluation of the sperm DNA normality appears to give more information in infertile patients with normal semen analysis. It may be a useful addition to the conventional semen analysis.
Several alpha, omega, di(2-methoxy-6-chloro-9-acridinyl) polyaza-alkanes have been prepared starting from 6, 9-dichloro-2-methoxy acridine. Some acridine dimers are able to bind to DNA with a very high affinity, both aromatic rings being intercalated.
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.
Effect of K- and L- molecular orbital regions on expression of antiplasmid and carcinogenic activity was studied with various benz[c]acridine derivatives, tricyclic compounds (acridine orange, phenothiazines) and dibenzoazepine (imipramine). Antiplasmid compounds showed the out-of-phase of molecular orbital in the L-region. On the other hand, mutagenic and carcinogenic compounds showed the out-of-phase in the L-region, and their energy was accumulated in the K-region of the molecular orbitals. The present study suggests that the molecular orbitals responsible for the expression of antiplasmid and carcinogenic effects might be basically different.
Smears of urethral and cervical discharge for direct microscopical examination of gonococci were stained with acridine orange and methylene blue and the findings compared with culture of direct inoculated plates. These two staining methods yielded similar results. Acridine orange staining seems a valuable alternative due to its sharp image contrast.
The mutagenicity of eleven methylbenz[c]acridines (methyl-B[c]ACRs) was examined by the direct Ames' Salmonella mutagenicity assay on the standard tester strains of TA97a, TA98, TA100 and TA102, each of which is specific to a certain type of mutation. The Benz[c]acridines (B[c]ACRs) studied in this investigation were substituted with one to three methyl group(s) at the 5, 7, 8, 9, 10 and 11 position(s) of B[c]ACR. A certain degree of mutagenic activity was observed by all methyl-B[c]ACRs on at least one of the tester strains, indicating that even non-carcinogenic methyl-B[c]ACRs showed mutagenicity in the assay. Meanwhile, 7,10-dimethyl-B[c]ACR and 7,9,10-trimethyl-B[c]ACR significantly increased the number of back-mutant colonies. However, monomethyl-B[c]ACRs, 7-methyl-B[c]ACR and 10-methyl-B[c]ACR did not increase back-mutation except for TA102 and TA100, respectively. The induction of 7-methyl substituent on B[c]ACR appears to play a key role in frameshift (+1 and -1), base-pair substitution, and single base substitution mutation of the strains in the presence of additional methyl substituent(s) at C-9 and/or C-10 position(s) of D ring of B[c]ACR.
In cooperation of 6 laboratories in Czechoslovakia and in the GDR, the efficiency of auramine-rhodamine B (AR) and acridine orange (AO) (short-time method) for staining of acid-fast bacilli was compared. Whereas a former comparison of AR and AO (original method) pointed out the superiority of AR, the investigation of both methods used as short-time procedures showed significantly more acid-fast rods after using AO. The number of "false positive" results was somewhat higher on AR staining. However the results depend not only on the method used but also on the procedure of staining and the optical equipment, and they are essentially influenced by the experience and proficiency of the microscopist. Taking into account the results of both studies both auramine-rhodamine B and acridine orange can be proposed for the staining of slides for microscopical detection of acid-fast rods. In case of AO, the short-time method is superior to the original long-time procedure.