Enhancement in vivo of the antiinflammatory and antitumor activities of type I interferon by association with the synthetic immunomodulator murabutide.
The therapeutic efficacy of type I interferon (IFN) has been reported to vary considerably in different indications. The use of the cytokine as adjuvant therapy has been suggested to enhance its efficacy and reduce the toxicity frequently associated with long-term and high-dose administration. In this study, we have assessed the activity of type I IFN in the protection against and treatment of acute hepatitis induced in mice by the administration of concanavalin-A (ConA). At the same time, we have evaluated the efficacy of the synthetic immunomodulator murabutide when administered alone or in combination with type I IFN to protect against ConA hepatitis and in the treatment of tumors in MethA sarcoma-bearing mice. Our results demonstrate a prophylactic effect as well therapeutic effects of type I IFN and of murabutide in the inflammation-mediated model of liver damage. The use of combination therapy presented enhanced efficacy in inhibiting the ConA-induced elevation of plasma transaminases. Both compounds were found to suppress IFN-gamma mRNA accumulation in the livers of ConA treated mice. This activity is discussed with respect to the mechanism of action of the two immunomodulators. In addition, the combination of murabutide with type I IFN exhibited synergistic antitumor activity that was clearly seen in the significant regression of MethA tumors and resulted in almost 50 percent tumor-free mice. The potential clinical application of combination therapies using a cytokine and a safe immunomodulator is analyzed in terms of enhancing the cytokine efficacy and extending its use to new indications.
Bahr
G M
GM
Vacsyn SA., 33, boulevard du General Martinal Valin, 75015 Paris, France.
Pouillart
P R
PR
Chedid
L A
LA
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D003208:Concanavalin A; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D007370:Interferon Type I / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C
D000276:Adjuvants, Immunologic; D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D007370:Interferon Type I; D003208:Concanavalin A; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C033575:murabutide; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase