Synergistic Effect of Rifamycin Derivatives and Amphotericin B on Viral Transformation of a Murine Cell Line

Hackett, Adeline J.; Sylvester, S. S.; Joss, Urs R.; Calvin, Melvin

doi:10.1073/pnas.69.12.3653

Cited by 21 publications

(10 citation statements)

References 11 publications

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“…This suggests that rough treatment of the nystatin-treated cells may damage the cell structure and release cytoplasmic components. DISCUSSION The polyene antibiotics nystatin and amphotericin B have been successfully used, at sublethal doses, to permeabilize yeasts (13,17) and other eukaryotic cells (1,7,9,14) towards small molecules and some inhibitors of macromolecular synthesis. The inhibitory synergism of amphotericin B with rifampin observed on Saccharomyces cerevisiae growth and RNA synthesis in vivo (2,13) has also been observed with the combination of nystatin and rifampin or streptolydigin on K. lactis (17).…”

Section: Resultsmentioning

confidence: 99%

Ribonucleic Acid Synthesis Dependent on Exogenous Triphosphates in Nystatin-Treated Cells of Kluyveromyces lactis

Badaracco

Cassani

1976

Antimicrob Agents Chemother

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Kluyveromyces lactis cells treated with nystatin became permeable to ribonucleoside triphosphates. Although not viable, nystatin-treated cells were capable of sustaining ribonucleic acid synthesis. The system depended on the presence of divalent ions and the four nucleoside triphosphates, and was strongly stimulated by ammonium sulfate. The system utilized endogenous deoxyribonucleic acid as template. Synthesis of ribonucleic acid was associated with the cells and probably occurred internally.

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Section: Resultsmentioning

confidence: 99%

Ribonucleic Acid Synthesis Dependent on Exogenous Triphosphates in Nystatin-Treated Cells of Kluyveromyces lactis

Badaracco

Cassani

1976

Antimicrob Agents Chemother

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“…Variation in culture conditions, serum concentration, and cell density undoubtedly play a role in such contradictory findings. For example, whether or not amphotericin B is present in culture medium may drastically change the result of focus inhibition (4,19). Furthermore, the high concentration of rifampicin used in these experiments (20-80 ug/ml) under some conditions is quite toxic to normal cells and makes interpretation of these data very difficult.…”

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confidence: 83%

“…The medium was changed on day 3. Secondary cultures were prepared 4 Measurements of the Rate of DNA and Protein Synthesis and Glucose Uptake. Radioactive assays were performed as described (25,26).…”

Section: Methodsmentioning

confidence: 99%

“…Rifamycin and its derivatives have been shown to inhibit focus formation by RNA tumor viruses in various cell types in culture (1)(2)(3)(4)(5). The in vitro demonstration that RNAdirected 'DNA polymerase is inhibited by the action of some of these derivatives (6)(7)(8)(9)(10)(11)(12)(13) has raised the possibility that the drugs may inhibit focus formation by inhibiting the activity of RNA-directed DNA polymerase.…”

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confidence: 99%

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Preferential Inhibition of the Growth of Virus-Transformed Cells in Culture by Rifazone-8 ₂ , a New Rifamycin Derivative

Bissell

Hatié

Tischler

et al. 1974

Proc. Natl. Acad. Sci. U.S.A.

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Rifampicin, a well-known derivative of rifamycin, has been shown to inhibit the replication of vaccinia virus in tissue culture when added at very high levels (>100 ug/ml) (15,16) and to reduce the incidence of adenovirus-induced tumors in male hamsters (16). In chick cells it has been argued that rifampicin (a) inhibits focus formation by Rous sarcoma virus (RSV) (1), (b) has no effect on transformation, as it is toxic to both normal and transformed cells (17), and (c) is preferentially toxic to transformed cells (20). Variation in culture conditions, serum concentration, and cell density undoubtedly play a role in such contradictory findings. For example, whether or not amphotericin B is present in culture medium may drastically change the result of focus inhibition (4, 19). Furthermore, the high concentration of rifampicin used in these experiments (20-80 ug/ml) under some conditions is quite toxic to normal cells and makes interpretation of these data very difficult. Rifampicin itself has little or no effect on activity of RNA-directed DNA polymerase in vitro at concentrations used in tissue culture studies (7,17,20). We have tested several new rifamycin derivatives synthesized in this laboratory that have been shown to be inhibitors of RNA-directed DNA polymerase in vitro and Abbreviations: R-82 or rifazone-82, rifaldehyde-N,N-di-n-octyl hydrazine-hydrazone; RSV, Rous sarcoma virus; B-RSV, Bryanhigh-titer strain of RSV; SR-RSV, Schmidt-Ruppin subgroup A strain of RSV; Rif, Rifampicin; DMB, 2',6'-dimethyl4'-benzyl-4'-desmethylrifampicin; (Me)2SO, dimethyl sulfoxide.inhibitors of focus formation in vivo in other cell systems (4-6).In addition, we have tested rifazone-82 (R-82), a new rifamycin which is to date the most selective inhibitor of viral RNAdirected DNA polymerase in vitro (6, 21). We find that at low concentrations (3-10 gg,ml), R-82 can selectively inhibit the growth of transformed cells and prevent focus formation while allowing the normal cell growth and function to continue. MATERIALS AND METHODSGrowth of Cell Cultures. Primary cultures were prepared from 10-day-old C/O or C/B type SPF chick embryos as described (23,24), except that amphotericin B (Fungizone) was eliminated at this point (25). The cells were seeded in medium 199, which was supplemented with tryptose phosphate broth (2%), calf serum (1%), and heated chicken serum (1%). The medium was changed on day 3. Secondary cultures were prepared 4 days after the primary seeding by trypsinization of primary cultures and were seeded at the desired cell concentration in 60-or 35-mm petri dishes. An additional 1 mg/ml of glucose was added to the medium at this time, bringing the final concentration of glucose to 11.00 mM, and calf-serum concentration was raised to 2%. For studies with transformed cultures, half the cells of a single embryo were infected 4 hr after primary seeding with 4 X 105 focusforming units of SR-RSV or B-RSV. Secondary cultures were prepared as above.Focus Assay. Assays were performed essentially as described (22), with sl...

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“…These antibiotics are known to potentiate various types of agents, including some antiviral compounds, attenuated viruses, and interferon inducers (1,5,16, 17). Specific polyene antibiotics are also able to differentiate in selective toxicity between virus-infected and uninfected cells (13).…”

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Combined effect of acyclovir and amphotericin B on the replication of pseudorabies virus in BHK-21 cells

Malewicz¹,

Momsen²,

Jenkin³

1983

Antimicrob Agents Chemother

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Acyclovir, known as an antiherpetic agent, showed an inhibitory effect on the propagation of pseudorabies virus in BHK-21 cells. The antiviral effect-of acyclovir was observed by plaque reduction, as well as by the inhibition of the virus-stimulated uptake of thymidine by BHK-21 cells. Amphotericin B potentiated the antiviral activity of acyclovir. The optimal concentrations of polyene antibiotic expressing the potentiating effect were lower than required for the induction of K+ leakage from the cells. There was no evident amphotericin Binduced stimulation of thymidine incorporation into infected BHK-21 cells. The model presented may be useful to study the potentiation phenomenon of polyene macrolide antibiotics.The ideal antiviral drug should specifically inhibit viral multiplication without expressing any toxic effect toward uninfected host cells. In general, however, all known antiviral agents that affect the multiplication of viral DNA or RNA also inhibit cell replication. Various methods have been developed to increase the discrimination threshold between virus inhibition and the cell toxicity of the drug. One method is a combined therapy of two agents which can produce additive, synergistic, or potentiating results, the last effect being the most desirable.Polyene macrolide antibiotics seem to be the agents of choice to study the potentiation phenomenon. These antibiotics are known to potentiate various types of agents, including some antiviral compounds, attenuated viruses, and interferon inducers (1,5,16, 17). Specific polyene antibiotics are also able to differentiate in selective toxicity between virus-infected and uninfected cells (13).The present paper reports the effect of the combined treatment of acyclovir [9(-2-hydroxyethoxymethyl)guanine] and amphotericin B on the propagation of pseudorabies virus in mammalian cells grown in culture.The antiviral activity of acyclovir against herpesviruses results from its affinity to thymidine kinase, which phosphorylates the acyclic guanine analog to acycloguanosine monophosphate and thence by other cell enzymes to the monophosphate, which is a competitive inhibitor of DNA polymerase (4).Results presented in this report indicate that amphotericin B potentiates the antiviral effect of acyclovir against pseudorabies virus. Porcine kidney cells (PK-15) were grown as a monolayer culture at 37'C in Eagle minimum essential medium (MEM) supplemented with 5% newborn calf serum. Cells were subcultured at weekly intervals. MEM supplemented with 1% newborn calf serum was used as a maintenance medium for virus propagation.Virus. Pseudorabies virus (Iowa strain) was originally obtained from Howard Hill (Iowa State University, Ames). The virus was serially propagated in PK-15 cells as follows. Cell monolayers (150 cm2) were washed with BSS and inoculated with 2 ml of pseudorabies virus at a multiplicity of infection equal to one. After cell-virus interaction for 60 min at 37'C, the virus inoculum was discarded, and 30 ml of the maintenance medium was added. After 48 to 72 h...

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Synergistic Effect of Rifamycin Derivatives and Amphotericin B on Viral Transformation of a Murine Cell Line

Cited by 21 publications

References 11 publications

Ribonucleic Acid Synthesis Dependent on Exogenous Triphosphates in Nystatin-Treated Cells of Kluyveromyces lactis

Ribonucleic Acid Synthesis Dependent on Exogenous Triphosphates in Nystatin-Treated Cells of Kluyveromyces lactis

Preferential Inhibition of the Growth of Virus-Transformed Cells in Culture by Rifazone-8 ₂ , a New Rifamycin Derivative

Combined effect of acyclovir and amphotericin B on the replication of pseudorabies virus in BHK-21 cells

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Synergistic Effect of Rifamycin Derivatives and Amphotericin B on Viral Transformation of a Murine Cell Line

Cited by 21 publications

References 11 publications

Ribonucleic Acid Synthesis Dependent on Exogenous Triphosphates in Nystatin-Treated Cells of Kluyveromyces lactis

Ribonucleic Acid Synthesis Dependent on Exogenous Triphosphates in Nystatin-Treated Cells of Kluyveromyces lactis

Preferential Inhibition of the Growth of Virus-Transformed Cells in Culture by Rifazone-8 2 , a New Rifamycin Derivative

Combined effect of acyclovir and amphotericin B on the replication of pseudorabies virus in BHK-21 cells

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Preferential Inhibition of the Growth of Virus-Transformed Cells in Culture by Rifazone-8 ₂ , a New Rifamycin Derivative