Binding Specificity and Affinity of Acriflavine for Nucleic Acids

Röth, Daniel; London, Morris; Manjon, Maria

doi:10.3109/10520296709114994

Cited by 20 publications

(11 citation statements)

References 8 publications

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“…Among the possible mechanisms postulated above, energy depletion is highly likely to be associated with the synergistic enhancement of acriflavine anti-tumour effects by guanosine. The acriflavine binding sites in the plasma membrane would include polymeric molecules of phosphate, sulphate, or carboxyl groups, or combinations of these (Roth et al 1967). Inhibition of the active site was overcome by the addition of triton X-100 micelles or phospholipid (e.g.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Anti-tumour Effects of Acriflavine in Combination with Guanosine in Mice

Kim

Ahn

et al. 1997

Journal of Pharmacy and Pharmacology

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The anti-tumour activity of acriflavine in combination with guanosine has been evaluated in solid or ascitic tumour-implanted animal models. Guanosine is known to potentiate the anti-tumour effects of some chemotherapeutic agents. Administration of acriflavine (15 mg kg-1 day-1, i.m., 14 days) to ICR mice subcutaneously implanted with Ehrlich carcinoma resulted in approximately 30% inhibition in tumour growth. In contrast, minor tumour growth inhibition was observed in animals treated with guanosine at the same daily dose. Treatment of animals with both acriflavine and guanosine (AG60, 1:1, w/w) at 30 mg kg-1 resulted in approximately 65% inhibition in tumour growth rate. Whereas treatment with acriflavine or guanosine resulted in 70% or 30% decrease in tumour weight, respectively, treatment of tumour-implanted mice with AG60 (30 mg kg-1) resulted in a 96% decrease in tumour weight, relative to control, 14 days after tumour-cell implantation. Dose-related inhibition in tumour growth rate was also observed in animals treated with AG60, with maximum (65%) inhibition noted at a dose of 30 mg kg-1 (ED50 23 mg kg-1). Suppression of body weight increase and elevated plasma glucose levels by acriflavine or AG60 indicated that glucose utilization might be impaired. The anti-tumour effect of AG60 was also determined in CDF1 mice intraperitoneally implanted with Ehrlich ascitic tumour. Ehrlich ascitic tumour proliferation was completely suppressed by AG60 (30 mg kg-1, i.p.). Microscopic analyses of intraperitoneal touch-prints revealed that AG60 was more effective in suppressing tumour proliferation than acriflavine alone. Fluorescent microscopic examinations demonstrated that acriflavine avidly bound with Yac-1 cell plasma membrane, leading to morphological changes in the cells, such as bleb formations, swelling and ballooning. The time-related changes in tumour cell morphology by acriflavine or AG60 might represent energy depletion, followed by osmotic lysis as a result of cationic influx. Enhanced anti-tumour activity of acriflavine in combination with guanosine might be explained by the blocking of nutrient transport through selective acriflavine binding with plasma membrane and by concomitant guanosine perturbation of cellular ATP production. This study demonstrates that guanosine enhances the anti-tumour effects of acriflavine against a variety of cancer cells without serious adverse effects, providing a preclinical basis for potential application of this combination against cancer proliferation.

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Section: Discussionmentioning

confidence: 99%

Enhanced Anti-tumour Effects of Acriflavine in Combination with Guanosine in Mice

Kim

Ahn

et al. 1997

Journal of Pharmacy and Pharmacology

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“…The avid binding of these compounds to the plasma membrane might induce respiratory deficiency in tumor cells. The membrane binding of ACF inhibits protein kinase C through interaction with regulatory lipid cofactors or the regulatory domain of the protein (Ferey et al, 1986;Roth et al, 1967); this might be one mechanism by which ACF has antitumor effects (Hannun and Bell 1988).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of guanosine in rats following intravenous or intramuscular administration of a 1:1 mixture of guanosine and acriflavine, a potential antitumor agent

et al. 2008

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A 1:1 mixture of acriflavine (ACF; CAS 8063-24-9) and guanosine is under evaluation in preclinical studies as a possible antitumor agent. Guanosine is known to potentiate the anti-cancer activity of ACF. We therefore investigated the pharmacokinetics of guanosine following administration of the ACF/guanosine mixture in rats. Rats were given guanosine (1 or 5 mg/kg) or ACF/guanosine (2 or 10 mg/kg) by i.v. bolus; or guanosine (3 or 15 mg/kg) or ACF/guanosine (6 or 30 mg/kg) by i.m. injection. We found that guanosine was rapidly cleared from the blood and transferred to tissues after i.m. administration of ACF/guanosine. The mean plasma half-lives (t(1/2)) at the alpha and beta phases were 0.091 and 6.86 h, or 0.09 and 7.51 h at a dose of 1 or 5 mg/kg guanosine, respectively. ACF had no effect on the plasma disappearance of guanosine following either i.v. bolus or i.m. administration of the combination mixture. Moreover, the ACF combination with guanosine did not significantly alter the values of MRT, V(dss), and CL(t) of guanosine. Guanosine exhibited linear pharmacokinetics over the dose range from 1 to 5 mg/kg for i.v. doses and 3 to 15 mg/kg for i.m. doses. The bioavailability of guanosine after i.m. administration was 84% for 3 mg/kg dose and 88% for 15 mg/kg dose. ACF had no effects on biliary and urinary excretion of guanosine after i.m. administration. The cumulative amount of guanosine in urine after i.m. administration was about 5-fold larger than that in bile, indicating that guanosine is mostly excreted into the urine. Guanosine was widely distributed in all tissues examined in this study, but was most highly concentrated in the kidney after i.m. administration, followed by slow excretion to bile or urine. ACF had no effect on the tissue distribution of guanosine following i.m. administration. These characterizations of the pharmacokinetics of guanosine after administration of the ACF/guanosine combination will be useful in providing preclinical and clinical bases for the potential application of this combination to the treatment of cancer.

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“…Because the dye binds to cellular DNA with near-stoichiometry and high specificity under these conditions, the amount of acriflavine lost from the supernate equals the amount taken up by the DNA of the entire cell population. 3 Dye concentrations were determined on an Aminco Fluoro-Microphotometer equipped with a 4 watt mercury lamp and Corning glass filters, CS 5-74 and 4-105, for the exciting and emitted beams of light, respectively. Results were recorded as the proportion (in per cent) of the dye taken up from the acriflavine solution by each sample of 50,000 cells.…”

Section: Methodsmentioning

confidence: 99%

Effectiveness of acridine-binding method in screening for oral, pharyngeal, and laryngeal cancer

Röth

Hayes

Ross³

et al. 1972

Cancer

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A method which indicates the DNA content of populations of desquamated buccal cells by measuring the amount of acriflavine they bind was evaluated for its effectivenes in identifying individuals with squamous cell carcinoma of the oral cavity, pharynx, or larynx. Comparisons of the frequency distributions for uptake of acriflavine by 50,000‐cell samples were made among 209 ostensibly healthy adults, 200 alcoholics, and 164 patients with cancer histories. Sufficient deviation from the noncancer groups was exhibited by the cancer group to suggest clinical exploitability for the method, particularly by health screening programs. At the 30% level for dye uptake, 96% of cases of existing cancer were identified. A false‐positive rate of 25% occurred at this level. Some false‐positive results were attributable to such possibly relevant conditions as viral infection and cigarette smoking.

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Binding Specificity and Affinity of Acriflavine for Nucleic Acids

Cited by 20 publications

References 8 publications

Enhanced Anti-tumour Effects of Acriflavine in Combination with Guanosine in Mice

Enhanced Anti-tumour Effects of Acriflavine in Combination with Guanosine in Mice

Pharmacokinetics of guanosine in rats following intravenous or intramuscular administration of a 1:1 mixture of guanosine and acriflavine, a potential antitumor agent

Effectiveness of acridine-binding method in screening for oral, pharyngeal, and laryngeal cancer

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