Biological and clinical effects of the combination of β- 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

Research output: Contribution to journalArticle

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Abstract

A phase I trial involving continuous infusion of both β- and γ-interferon (IFN-β and IFN-γ) was conducted in 20 patients in order to determine whether combinations of high doses of IFN-β and IFN-γ were tolerable when administered under conditions which mimic conditions of in vitro antiproliferative studies. Patients received a 5-day continuous infusion of IFN-β/IFN-γ, followed by a 9-day rest period. Two cycles were administered. Doses of IFN-β/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-β/IFN-γ infusion was 3 × 106 units of IFN-β and 200 μg of IFN-γ. Dose-limiting side effects consisted of severe headache, fatigue, fever, and hepatic toxicity. No clinical responses were observed. 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-inducibte 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 β2-microglobulin, 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 β2-microglobulin, neopterin, and p78 (P < 0.02). We retrospectively compared the results of this trial with those of another IFN-β/IFN-γ trial in which IFN-β 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-β 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-β 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

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Interferons
Serum
Neopterin
Appointments and Schedules
Ligases
Maximum Tolerated Dose
Tryptophan
Fatigue
Headache
Fever
Therapeutics
Liver
Proteins
2',5'-oligoadenylate
In Vitro Techniques

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Schiller, J. H., Storer, B., Witt, P. L., Nelson, B., Brown, R. R., Horisberger, M., ... Borden, E. C. (1990). Biological and clinical effects of the combination of β- and γ-interferons administered as a 5-day continuous infusion. Cancer Research, 50(15), 4588-4594.

Biological and clinical effects of the combination of β- and γ-interferons administered as a 5-day continuous infusion. / Schiller, Joan H.; Storer, Barry; Witt, Patricia L.; Nelson, Beth; Brown, Raymond R.; Horisberger, Michel; Grossberg, Sidney; Borden, Ernest C.

In: Cancer Research, Vol. 50, No. 15, 01.08.1990, p. 4588-4594.

Research output: Contribution to journalArticle

Schiller, JH, Storer, B, Witt, PL, Nelson, B, Brown, RR, Horisberger, M, Grossberg, S & Borden, EC 1990, 'Biological and clinical effects of the combination of β- and γ-interferons administered as a 5-day continuous infusion', Cancer Research, vol. 50, no. 15, pp. 4588-4594.
Schiller JH, Storer B, Witt PL, Nelson B, Brown RR, Horisberger M et al. Biological and clinical effects of the combination of β- and γ-interferons administered as a 5-day continuous infusion. Cancer Research. 1990 Aug 1;50(15):4588-4594.
Schiller, Joan H. ; Storer, Barry ; Witt, Patricia L. ; Nelson, Beth ; Brown, Raymond R. ; Horisberger, Michel ; Grossberg, Sidney ; Borden, Ernest C. / Biological and clinical effects of the combination of β- and γ-interferons administered as a 5-day continuous infusion. In: Cancer Research. 1990 ; Vol. 50, No. 15. pp. 4588-4594.
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