Interferon inducer, polyriboguanylic.polyribocytidylic acid, inhibits experimental hepatic metastases in mice.

The antitumour activity of an interferon inducer, the double-stranded complex of polyriboguanylic.polyribocytidylic acid was studied on murine lymphosarcoma LS/BL. The antitumour effect was determined with the aid of an experimental liver-colony model and compared to that exhibited by another synthetic RNA, polyriboinosinic.polyribocytidylic acid. We found that both polynucleotide complexes decreased the number of liver colonies and prolonged the survival of the tumour-bearing mice. This effect was only observed if the complexes were applied in an appropriate dose schedule which included the administration of the drug prior to tumour cell inoculation and subsequent continuous treatment. We have also verified that the polynucleotide complexes did not exert their antitumour effect by a direct action on tumour cells.

[Dependence of the antiviral activity of the poly(G).poly(C) complex on the size of the continuous poly(C)segments]. / Zavisimost' protivovirusnoi aktivnosti kompleksa poli(G).poli(Ts) ot razmera nepreryvnykh uchastkov poli(Ts).

Modification of poly(C) by various frequency treatment with adenosine non-complementary to guanosine has produced poly(G) X poly (C.A) complexes with continuous double-stranded areas the length of which is determined by C/A ratio. Studies of the antiviral activity of poly(G).poly(C,A) complexes with C/A from 10:1 to 90:1 and poly(G).poly(C) in vesicular stomatitis virus-infected chick embryo cell cultures and in experimental tick-borne encephalitis of mice demonstrated that the maximum activity is achieved at an average lengths of double-stranded areas of 90 nucleotide pairs. At the same time, a low but statistically significant antiviral activity is observed at a length of double-stranded areas of 10-30 nucleotide pairs.

[Evaluation of the size of the continuous poly(G) site necessary for the biological activity of the poly(G).poly(C) complex]. / Otsenka razmera nepreryvnogo uchastka poli(G), neobkhodimogo dlia biologicheskoi aktivnosti kompleksa (G).poli(Ts).

On the basis of synthesis of a series of poly(G, A).poly(C) copolymers with changing G:A ratio from 15:1 to 90:1 and trials of their biological activity in comparison with poly(G).poly(C), the size of poly(G) in it was evaluated within the range of a continuous double-stranded area necessary for the activity. The antiviral activity close to that of poly(G).poly(C) in experimental tick-borne encephalitis of mice and vesicular stomatitis virus infection of chick embryo cells was found only in poly(G,A).poly(C) complexes with a G:A ratio equal to or higher than 90:1. Consequently, the high activity of poly(G).poly(C) is present at an average length of poly(G) equal to 90-100 nucleotides within the limits of the continuous double-stranded area.

[Effect of virazole on the antiviral activity of poly(G) X poly(C) and other polyribonucleotide interferonogens]. / Vliianie virazola na protivovirusnuiu aktivnost' poli(G) X poli(Ts) i drugikh poliribonukleotidnykh interferonogenov.

The effect of virazole on the antiviral activity of poly (G) X poly (C), poly (G, A) X X poly (C) and poly(G, I) X poly (C) was studied in cell cultures and on mice. It was shown that virazole in concentrations not sufficient for significant inhibition of the development of vesicular stomatitis virus or Sindbis virus in chick embryo cell cultures markedly increased the antiviral effect and allowed decreasing the minimum effective doses of the synthetic polyribonucleotide complexes with respect to the above viruses. Combined administration of poly (G) X poly (C) and virazole to mice 1-2 or 24 hours after infection with tick-borne encephalitis virus provided a much more pronounced decrease in the death rate of the animals than the use of the interferonogen alone. Virazole per se was little active and had no significant effect on the intensity of interferonogenesis promoted by the use of poly (G) X poly (C). A possibility of successful therapy of viral infections with polyribonucleotide interferonogens in combination with virazole or other chemotherapeutic drugs with broad antiviral spectrum is discussed.

[Combined antiviral effect of synthetic polyribonucleotide interferonogens and specific antiviral antibodies in arbovirus infections]. / Kombinirovannyi protivovirusnyi éffekt sinteticheskikh poliribonukleotidnykh interferonogenov i spetsificheskikh protivovirusnykh antitel pri arbovirusnykh infektsiiakh.

A model of tick-borne encephalitis in BALB/c mice was used to investigate the protective anti-viral effect of an interferon inducer, poly(G).poly(C), and specific gamma-globulin administered to the animals together or separately in small doses 24 hours before or after virus inoculation. Administration to the animals of poly(G).poly(C) alone or gamma-globulin alone was shown to produce a poor protective effect. Simultaneous administration of both preparations resulted in a significant decrease of mouse mortality after infection. As a result of the pretreatment of chick embryo cell cultures with poly(G).poly(C) before inoculation and the addition of specific immune serum to the agar overlay after the Sindbis virus inoculation, its multiplication was inhibited much more than after treatment of the cells with interferon inducer alone or antibody alone. Possible mechanisms of the observed additive antiviral effects of the interferon inducer and antibody, including those associated with the influence on the virus-induced interferon production, as well as the possibility of their combined use for the prevention and treatment of viral infections are discussed.

[Protective action of double-stranded complexes--interferon inducers in encephalomyocarditis in mice]. / Zashchitnoe deistvie dvunitevykh kompleksov--induktorov interferona pri éntsefalomiokardite myshei.

Interferon inducers, dsRNA and poly (G) X poly (C) ( polyguacyl ), injected into mice intraperitoneally induced interferon formation, the maximal activity being equal to 640-1280 U/ml. Antiviral effect of the inducers was studied upon intraperitoneal and intracerebral injections. Both polyguacyl and dsRNA exerted a marked antiviral action against infection induced by murine encephalomyocarditis virus. The most powerful effect was attained when the inducers were injected 24 or 4 h before challenge. The protective action was produced by polyguacyl and dsRNA even after intracerebral infection. There is a good agreement between the interferon-inducing and antiviral activity of interferon inducers. The data obtained demonstrate the fitness of experimental encephalomyocarditis of mice for testing interferon inducers.

[Immunostimulating effect of interferon inducers]. / Immunostimuliruiushchii éffekt induktorov interferona.

The effect of interferon inducers on the immune response to vaccination was determined. The prophylactic effect of interferon inducers in combination with vaccines was determined with regard to experimental influenza, the therapeutic effect with regard to rabies and tick-borne encephalitis. Despite the differences in the experimental design (administration of the inducers before, after, or together with vaccines), the additive or synergistic effect was regularly observed with a 2-6-fold increase in the level of protection of the animals infected with the appropriate viruses as compared with the use of vaccines or interferon inducers separately. The protective effect depends a lot on the concentration, site and time of inoculation of the preparations, multiplicity of infection, and some other conditions.

[Thermoactivation of poly(G).poly(C): a description of the effect and its hypothetical mechanism]. / Termoaktivatsiia poli(G).poli(Ts): opisanie éffekta i ego predpolagaemyi mekhanizm.

Heating of poly(G).poly(C) complex solutions at a temperature about 100 degrees C was shown to overcome a decrease in the antiviral and interferon-inducing activity of the preparations which were obtained at relatively high concentrations of polynucleotides from poly(G) stored in solution, or were stored frozen themselves. These unfavourable conditions contributed to stabilization of the poly(g) secondary structure and decrease in the degree of regularity of the complex molecules. The results suggest that thermal activation of such poly (G). poly(C) preparations occurred in 2 stages by melting residual free regions of poly(G) and their subsequent interaction with poly(C) with formation of a more regular complex.

[Trial of polyguacyl safety and tolerance]. / Ispytanie bezvrednosti i perenosimosti poliguatsila.

The results of studies of the antiviral and interferon-inducing activity of the synthetic interferon inducer polyguacyl in white mice as well as the results of the study of safety and tolerance of this drug given to human subjects as aerosol and intranasally are presented. Both modes of administration to mice induced production of endogenous interferon, although after intranasal inoculation high interferon titres in the blood serum of the animals were observed for longer periods of time, whereas after aerosol administration interferon disappeared more rapidly. Significant antiviral protection was achieved only by the intranasal administration of the inducer resulting in 84.0% survival of the animals challenged with the mouse-adapted influenza A/Aichi virus. Clinical trials of polyguacyl in human volunteers demonstrated the safety and good tolerance of this drug given both as aerosol and intranasally.

[Interferon-inducing and protective action of polyguacyl in an experimental influenza infection]. / Izuchenie interferonindutsiruiushchego i zashchitnogo deistviia poliguatsila pri éksperimental'noi grippoznoi infektsii.

A comparative study of the interferon-inducing and anti-influenza activity of polyguacyl, an interferon inducer, given to human volunteers intranasally and as an aerosol, was carried out. The induction of endogenous interferon in the blood to 100-127 units/ml was observed only after intranasal administration of 5 mg polyguacyl. By both routes of administration the inducer did not diminish the implantation of the virus and development of postvaccination reactions in volunteers to intranasal administration of live influenza A (H1N1) vaccine.