Biological and Clinical Effects of the Combination of θ- and γ-Interferons Administered as a 5-Day Continuous Infusion

Joan H. Schiller, Barry Storer, Patricia L. Witt, Beth Nelson, Raymond R. Brown, Michel Horisberger, Sidney Grossberg, Ernest C. Borden

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Abstract

A phase I trial involving continuous infusion of both θ- and γ-interferon (IFN-θ and IFN-γ) was conducted in 20 patients in order to determine whether combinations of high doses of IFN-03B8; and IFN-03B3; were tolerable when administered under conditions which mimic conditions of in vitro antiproliferative studies. Patients received a 5-day continuous infusion of IFN-θ/IFN-γ followed by a 9-day rest period. Two cycles were administered. Doses of IFN-θ/IFN-γ were escalated between 4 dose levels, with 5 patients per dose level. Dose-dependent side effects, consisting primarily of constitutional symptoms typical of those experienced with IFN, were observed. The maximally tolerated dose of continuous IFN-0/IFN-7 infusion was 3 x 106 units of IFN-θ and 200 μ of IFN-γ. Dose-limiting side effects consisted of severe headache, fatigue, fever, and hepatic toxicity. No clinical responses were bserved. Serum IFN was measurable only at the highest 3 dose levels. Only 5 patients (4 at the highest dose level) had total serum levels which exceeded 50 laboratory units/ml (55, 63, 800, 800, and 550 laboratory units/ml, respectively). In order to confirm the biological effectiveness of this schedule, we measured IFN-inducible proteins prior to therapy, 24 h after the initiation of the infusion, and at the completion of the 5-day infusion. 2′–5–-Oligoadenylate synthetase, serum θ2-inicroglobulin, neopterin, and p78 levels all increased significantly, and serum tryptophan decreased significantly within 24 h after the initiation of treatment (P ≺ 0.0001). A dose-response effect was observed for serum θ2-microglobulin, neopterin, and p78(p≺0.02). We retrospectively compared the results of this trial with those of another IFN-θ/IFN-γ trial in which IFN-0 and IFN-γ were administered by i.v. bolus. Within the limitations of a retrospective comparison, continuous infusion was less well tolerated than our previous schedule of bolus administration 3 times/week. However, the continuous infusion schedule appeared to be more effective in enhancing 2′–5′-oligoadenylate synthetase levels in mononuclear cells. We conclude that tolerable doses of IFN-θ and IFN-γ do not result in serum IFN levels which produce significant synergistic antiproliferative responses in vitro. This study and other findings suggest that, unless higher doses can be achieved, combinations of IFN-θ and IFN-γ are unlikely to have significant therapeutic activity.

Original languageEnglish (US)
Pages (from-to)4588-4594
Number of pages7
JournalCancer research
Volume50
Issue number15
StatePublished - Aug 1 1990

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Schiller, J. H., Storer, B., Witt, P. L., Nelson, B., Brown, R. R., Horisberger, M., Grossberg, S., & Borden, E. C. (1990). Biological and Clinical Effects of the Combination of θ- and γ-Interferons Administered as a 5-Day Continuous Infusion. Cancer research, 50(15), 4588-4594.