The Mode of Action of Phenanthridines: The Effect of Ethidium Bromide on Cell Division and Nucleic Acid Synthesis

Newton, B.A.

doi:10.1099/00221287-17-3-718

Cited by 91 publications

(34 citation statements)

References 13 publications

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“…The fact that T. rhodesiense multiplies more rapidly than T. congolense in the mouse suggests that the compounds might be removed more quickly to the secondary binding sites in the former species if they interfere with deoxyribonucleic acid metabolism, as homidium does in Strigomonas oncopelti (Newton, 1957(Newton, , 1964.…”

Section: Resultsmentioning

confidence: 99%

“…In terms of the hypothesis put forward by Newton (1957) to explain uptake of homidium by Strigomonas oncopelti, a greater rate of uptake of the three compounds by T. rhodesiense compared with T. congolense could be due to a differential affinity of the compounds for the primary binding sites of the two species, to their unequal rate of removal to the secondary binding sites, or to a combination of both these factors. The fact that T. rhodesiense multiplies more rapidly than T. congolense in the mouse suggests that the compounds might be removed more quickly to the secondary binding sites in the former species if they interfere with deoxyribonucleic acid metabolism, as homidium does in Strigomonas oncopelti (Newton, 1957(Newton, , 1964.…”

Section: Resultsmentioning

confidence: 99%

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Studies on Isometamidium: The Effect of Isometamidium, Homidium and Pyrithidium on the Infectivity of Trypanosomas for Mice

Hill

1965

British Journal of Pharmacology and Chemotherapy

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During the course of an investigation into the antitrypanosomal activity of isometamidium, some phenanthridinium compounds were administered to mice infected with Trypanosoma rhodesiense or T. congolense; trypanosomes from these mice were subinoculated into fresh mice at various times after treatment, and the effect of the compounds on infectivity was noted. In vivo/in vivo experiments of this kind have been carried out in the past by Lock (1950) with dimidium bromide and T. congolense and by Ormerod (1951) with antrycide and T. equiperdum. These authors also carried out in vitro/in vivo experiments similar to those described below, as did Hawking (1939) with suramin and T. rhodesiense. But so far no one seems to have compared the activities of compounds against different species of trypanosome by either of these methods. METHODSThe Lugala II strain of T. rhodesiense was used. This was isolated in Uganda in 1955 and received by us from EATRO in 1958. Since then it has been passaged by blood inoculation through mice, which it kills in 3 to 4 days. The strain of T. congolense was an old laboratory one which produces an acute or subacute infection in mice, killing them in 7 to 20 days (Brown, Hill & Holland, 1961).Mice were infected intraperitoneally with approximately 750,000 trypanosomes each in 0.2 ml. of citrate-saline, as in a normal therapeutic experiment. They were treated with homidium, isometamidium or pyrithidium (Prothidium) 1 or 2 days later, when there were 1 to 10 trypanosomes per high power field in the peripheral blood-stream. One mouse was left untreated, as a control, in each experiment. At 2, 24 or 48 hr after treatment blood was taken from the tail of the treated mice with a syringe and a No. 18 hypodermic needle, diluted with citrate-saline and injected intraperitoneally into previously untreated and uninfected mice. Three such mice were subinoculated from each donor. Bloods from different donors were not mixed. Three control mice were similarly infected from the untreated control donor referred to above.Beginning 4 to 5 days after subinoculation, the peripheral blood of the donor and subinoculated mice was examined three times a week for up to 28 days after subinoculation. Failure to detect trypanosomes during this period in a donor was taken as an indication that it had been cured, or in a subinoculated mouse as an indication that the trypanosomes in the inoculum had been noninfective due to their exposure to the drug before subinoculation.Some preliminary experiments with T. congolense and isometamidium failed to reveal any difference between the effects on infectivity of the intravenous and subcutaneous administration of the drug, so the subcutaneous route was used in the later work with both parasites and all three compounds.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Studies on Isometamidium: The Effect of Isometamidium, Homidium and Pyrithidium on the Infectivity of Trypanosomas for Mice

Hill

1965

British Journal of Pharmacology and Chemotherapy

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“…produces dyskinetoplasia in hemoflagellates (Newton, 1957(Newton, , 1964Steinert, 1969) . Mcllwain (1941) demonstrated that adenine interferes with acr's effects in bacteria .…”

Section: Discussionmentioning

confidence: 99%

“…The tolerance of the B strain could be raised to 480 ng/ml EB, if the amount of hemin in medium C were doubled to 40,ug/ml . Thus, hemin played a role in the mode of action of a second agent known to cause dyskinetoplasia in hemoflagellates (Newton, 1957(Newton, , 1964Steinert, 1969 ;Steinert et al ., 1969) . From the B strain, cultures were obtained that were resistant both to 470 ng/ml acr and 260 ng/ml EB together (A-B strain) .…”

Section: Table IXmentioning

confidence: 99%

ACRIFLAVIN RESISTANCE IN THE HEMOFLAGELLATE, LEISHMANIA TARENTOLAE

Strauss

1972

The Journal of Cell Biology

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The accumulation, metabolism, and distribution of acriflavin (acr) in two culture strains of Leishmania tarentolae were studied . One strain, reported previously, was sensitive to the dye, i .e . became dyskinetoplastic and could not be subcultured in the presence of 470 ng/ml acr, and one was resistant . Accumulation was studied by fluorescence of the dye within cells and by uptake of acr-3 H by cells . Metabolism was studied by paper chromatography of aqueous extracts from cells grown with acr-3 H, and distribution was examined by fluorescence and quantitative electron microscope radioautography . Substances affecting the response to acr included heroin and an acr-sensitizing factor initially obtained from red cells but here shown to be distinct from hemoglobin . In the presence of the sensitizing factor or in the absence of hemin, the resistant strain became dyskinetoplastic and could not be subcultured . Acr fluorescence appeared in the nucleus of the resistant strain, and the percentage of radioautography grains appearing in the nucleus increased . Under these conditions the distribution of radioactivity from chromatographed extracts was altered from the normal in a similar fashion .

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“…It was of interest to determine whether the drug could supply R. TOMCHICK AND H. G. MANDEL information on similar compartmentation in micro-organisms. The compound had been shown to inhibit DNA synthesis preferentially in a trypanosomal flagellate (Newton, 1957), and to depress RNA and DNA formation to a greater extent than that of protein in yeast cells (Kerridge, 1958). The drug's actions were therefore evaluated in a Gram-positive organism, Bacillus cereus, and a Gram-negative organism, Escherichia coli, in an effort to uncover dissociation of biosynthetic processes during inhibition of growth.…”

Section: Introductionmentioning

confidence: 99%

Biochemical Effects of Ethidium Bromide in Micro-organisms

Tomchick

Mandel

1964

Journal of General Microbiology

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SUMMARYGrowth of Escherichia coli was partially inhibited by 1.2 x lo-* Methidium bromide, a phenanthridinium trypanocide. In the presence of manganese the drug's effect was decreased. During growth in the presence of ethidium, RNA and protein contents were relatively unaffected when comparison was made between experimental and control cultures a t similar turbidities ; DNA content, on the other hand, was considerably decreased. A differential effect of ethidium on the formation of polynucleotide pyrimidines from labelled uracil and orotic acid was observed. Oxygen uptake continued almost unchanged during growth whether in the presence or absence of drug.Bacillus cereus was extremely sensitive to the growth-inhibitory action of ethidium ( ~W M ) and morphological changes were observed. Manganese protected ,the organisms from the drug's actions. RNA and DNA biosynthesis were both suppressed during inhibition of growth to a greater extent than was total protein formation, whereas diaminopimelic acid incorporation into cell wall and oxygen uptake continued almost unaffected. Some evidence was obtained that the pattern of protein synthesis was disturbed.It was concluded that the drug's actions were species dependent, and that the effect on Escherichia coli resembled that described for a flagellate, while that on Bacillus cereus did not. Evidence for compartmentation of nucleic acid synthesis, as obtained with the drug in tumour cells, was not shown for either micro-organism.

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The Mode of Action of Phenanthridines: The Effect of Ethidium Bromide on Cell Division and Nucleic Acid Synthesis

Cited by 91 publications

References 13 publications

Studies on Isometamidium: The Effect of Isometamidium, Homidium and Pyrithidium on the Infectivity of Trypanosomas for Mice

Studies on Isometamidium: The Effect of Isometamidium, Homidium and Pyrithidium on the Infectivity of Trypanosomas for Mice

ACRIFLAVIN RESISTANCE IN THE HEMOFLAGELLATE, LEISHMANIA TARENTOLAE

Biochemical Effects of Ethidium Bromide in Micro-organisms

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