Recombinant Leukocyte A Interferon: Pharmacokinetics, Single-Dose Tolerance, and Biologic Effects in Cancer Patients

Abstract

Sixteen patients with advanced cancer were treated with recombinant-DNA-produced pure leukocyte A interferon (IFLrA) intramuscularly in doses ranging from 3 to 198 X 10(6) units. with interval periods of 72 to 96 hours between doses. At the two lowest doses of 3 and 9 million units, there was a cross-over evaluation between IFLrA and partially pure leukocyte interferon (IFN-C) produced from human cells. THe maximum observed serum concentration of IFLrA measured by enzyme immunoassay and bioassay increased with increasing doses. The mean serum concentrations of IFLrA and IFN-C were similar. Clinical effects produced by IFLrA and IFN-C were similar, including fever, chills, myalgias, headache fatigue, and reversible leukopenia and granulocytopenia. Eight patients had transient and mild numbness of the hands or feet, or both. Three patients developed low titers of antibody to IFLrA, Seven of 16 patients showed objective evidence of tumor regression during the study.

Negative Immunoregulatory Effects of Antidepressants Inhibition of Interferon-γ and Stimulation of Interleukin-10 Secretion

“…Humans with increased IFN␥ and decreased IL-10 secretion and, consequently, all increased IFN␥/IL-10 ratio, show significant stress-induced increments in depression and anxiety (Maes et al 1998b). Finally, administration of interferons, including IFN␥, results in behavioral effects and mood alterations, including symptoms reminiscent of depression and anxiety (Smith 1991;Gutterman et al 1982;Weinberg et al 1988). Because antidepressants decrease the IFN␥/IL-10 ratio, it may be speculated that antidepressants exert some of their antidepressant effects through their negative immunoregulatory capacities.…”

Lowered Serum Dipeptidyl Peptidase IV Activity is Associated with Depressive Symptoms and Cytokine Production in Cancer Patients Receiving Interleukin-2-Based Immunotherapy

“…The psychiatric side effects of IFN ␣ therapy are irritability, crying spells, agitation, anhedonia, anorexia, weight loss, anxiety, social withdrawal, psychomotor retardation, anergy, sleep disturbances and malaise, full blown mood disorders, mostly depression but also mania, suicide, and relapse in drug and alcohol abuse. Moreover, major depression is reported in high frequency as a reason for dose reduction or for stopping immunochemotherapy (Gutterman et al 1982;Janssen et al 1994a;Kirkwood et al 1996;Guilhot et al 1997;Grob et al, 1998;McHutchison et al 1998;Davis et al 1998;Valentine et al 1998;Van Gool et al 1999). Treatment of cancer patients with IL-2 increases the plasma concentrations of IL-6 and the soluble IL-2 receptor (IL-2R), a T cell activation marker, whereas IFN ␣ increases plasma IL-2 (Janssen et al 1994b;Meffert et al 1994;Taylor and Grossberg 1998).…”

Recombinant interferon in advanced breast cancer

“…It was initially planned to study 60 patients but the study was stopped at 15 in view of the poor response rate. This dose was based on previously reported phase I studies (Gutterman et al, 1982). Dose reductions to 50% and then 10% of the above doses were made in patients with toxic side effects.…”