Apparent New Modes of Antimalarial Action Detected by Inhibited Incorporation of Adenosine-8-3H into Nucleic Acids of Plasmodium berghei

Dyke, Knox Van; Szustkiewicz, C.

doi:10.1093/milmed/134.9.1000

Cited by 22 publications

(9 citation statements)

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“…4). The dra matic effect of quinacrine (1 0~4m ) on the uptake of tritiated adenosine by a pool of parasitized (17 °/o) red blood cells has already been noted [6]. Interestingly the drug 4,4' diaminodiphenyl sulfone is inhibitory only at the parasitized-cell level with no effect on the 'free' parasite [6].…”

Section: Resultsmentioning

confidence: 99%

“…Recently it has been possible to prepare 'free' parasites which have the equivalent or greater ability to incorporate adenosine-8-3H than parasites existing in their host red cells [6]. When quinacrine was added to these 'free' parasite preparations it was still highly effective ( fig.…”

Section: Resultsmentioning

confidence: 99%

“…Pre liminary investigations [6,7] made in conjunction with studies presented within this paper have established the biochemical rationale and the basic incubation conditions for an optimally efficient test system in terms of time, temperature, and pH; also the amount of radioactivity and the amount of blood per tube were critically assessed in terms of ease of han dling and economy.…”

Section: Discussionmentioning

confidence: 99%

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A Unique Antinuclcic Acid Approach to the Mass Screening of Antimalarial Drugs

Dyke¹,

Szustkiewicz²,

Cenedella³

et al. 1970

Chemotherapy

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The antimalarial-drug-screening system described herein represents the first practical mass-screening system dealing selectively and reproducibly with parasite-nucleic acids. No complicated separation of cell types or separation of nucleic acid types is necessary. Antinucleic-acid-antimalarial potential can be recognized in 1½ h of experimental time. Structure-activity and dose-response relationships are easily studied. The system can test drugs against both intraerythrocytic and ‘free’ parasites and this use has revealed that certain drugs have antimalarial actions that are mediated through effects upon the host cell membrane. Finally all data can be processed simply by computer analysis therefore making calculations and retrieval of information extremely rapid.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Unique Antinuclcic Acid Approach to the Mass Screening of Antimalarial Drugs

Dyke¹,

Szustkiewicz²,

Cenedella³

et al. 1970

Chemotherapy

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“…It is unlikely that the phosphorylated derivatives could serve as precursors since nucleotides do not readily pass membranes (Leibman and Heidelberger, 1955;Roll et al, 1956;Hoffman and Okita, 1965). Studies involving adenine and adenosine passage through membranes (Jacob and Berne, 1970;Van Dyke et al, 1969;Kolassa, 1970) have demonstrated that adenosine is more readily taken up and phosphorylated than is adenine. Recent studies in our laboratory (Stevens et al, 1972) have detailed the first successful attempt to rapidly label the ATP of the chromaffin granules by using adenosine-8-3H as a precursor.…”

Section: Discussionmentioning

confidence: 99%

Synthesis, Storage and Drug-Induced Release of ATP-8-<sup>3</sup> H in the Perfused Bovine Adrenal Gland

Stevens¹,

Robinson²,

Dyke³

et al. 1975

Pharmacology

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The perfused bovine adrenal gland was able to take up and phosphorylate adenosine-8-³H. Stimulation of the gland with carbachol resulted in a simultaneous release of catecholamines, adenosine-8-³ H and labelled adenine nucleotides including a small quantity of ATP-³H. A direct demonstration of the presence of ATP-³H in isolated chromaffin granules was obtained by modified sucrose density gradient centrifugation. Glands were also perfused with a Ca⁺⁺-Mg⁺⁺-free-EDTA medium to inhibit adenosine triphosphatases. Using this medium, significant amounts of ATP-³ H and endogenous ATP were found in the effluent after drug stimulation by either Ba⁺⁺ or aminophylline. Under Ca⁺⁺-Mg⁺⁺-free-EDTA conditions both Ba⁺⁺ and aminophylline, but not carbachol, stimulated the release of catecholamines, ATP, ATP-³H with no concomitant increase in total radioactivity. Using normal medium, Ba⁺⁺ caused the simultaneous release of catecholamines and radioactivity while aminophylline only induced the release of catecholamines. Specific activity measurements of drug-released ATP indicated that the newly synthesized ATP-³ H was being released preferentially during spontaneous activity while the endogenous ATP was preferentially released after either Ba⁺⁺ or aminophylline-induced secretion.

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“…The interaction with DNA may result in the inhibition of replication or transcription, and the interaction with RNA may result in the inhibition of translation. Chloroquine and primaquine inhibit the incorporation of radioactive precursors into DNA and/or RNA in non-mammalian eukaryotic cells (Schellenberg & Coatney, 1961;Polet & Barr, 1968; Dyke, Szustkiewicz, Lantz & Saxe, 1969;Conklin & Chou, 1972a) and in cultured mammalian cells (Gabourel, 1963;Epstein, Fukuyama & Epstein, 1971). In vitro, chloroquine and primaquine inhibit DNA and RNA polymerases from bacterial sources (Cohen & Yielding, 1965;O'Brien, Olenick & Hahn, 1966;Whichard, Washington & Holbrook, 1972;Marquez, Cranston, Ruddon & Burckhalter, 1974) and from Tetrahymena pyriformis (Conklin, Heu and Chou, 1973).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Precursor Incorporation Into Nucleic Acids of Mammalian Tissues by Antimalarial Aminoquinolines

Field

Gibson

Holbrook

et al. 1978

British J Pharmacology

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1 Chloroquine, primaquine and ethidium inhibited thymidine incorporation into deoxyribonucleic acid of rat tissues when administered concurrently with the labelled precursor. 2 Chloroquine and primaquine inhibited the incorporation of uridine and adenine, but not orotate, into various ribonucleic acid fractions of liver of rats and mice. These drugs had no effect on leucine incorporation into hepatic protein in rats or mice. 3 Although chloroquine and primaquine are active against different stages in the life cycle of the malarial parasites, the two aminoquinolines exert similar effects in rodent tissues.

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Apparent New Modes of Antimalarial Action Detected by Inhibited Incorporation of Adenosine-8-3H into Nucleic Acids of Plasmodium berghei

Cited by 22 publications

References 0 publications

A Unique Antinuclcic Acid Approach to the Mass Screening of Antimalarial Drugs

A Unique Antinuclcic Acid Approach to the Mass Screening of Antimalarial Drugs

Synthesis, Storage and Drug-Induced Release of ATP-8-<sup>3</sup> H in the Perfused Bovine Adrenal Gland

Inhibition of Precursor Incorporation Into Nucleic Acids of Mammalian Tissues by Antimalarial Aminoquinolines

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