Interferon*,†

Abstract

This paper describes our experience in the production, stabilization, and clinical application of mouse interferon. The interferons are species-specific, low molecular weight proteins elaborated by living cells in response to viral or other induction.' When the interferons made by these cells are applied to other cells of the same species, they inhibit or annul both viral propagation and viral transformation.2 Interferon protects cells against a wide variety of viruses; the prophylactic efficacy has been demonstrated often. We have found additionally, however, that interferon has an even broader area of competence. This paper presents evidence that interferon is a carcinolytic agent capable of destroying cells that have already been transformed by some earlier event. The therapeutic promise of interferon thus takes on a new dimension.The fulfillment of this promise depends not only on the demonstration of clinical efficacy, but also on the feasibility of producing interferon in useful amounts. Interferon is yielded by living cells both in vivo and in vitro. It appears at peak levels in the body fluids within a few hours after the administration of an interferogen to the animal, and then declines to nought within a few days. Repetitive administration of the inducer, even were it not prohibitively toxic, as it often is, is only negligibly productive. Cells in vitro respond similarly, are restricted to one cycle of interferon production, and cannot be used again. The difficulties, or anticipated difficulties, of growing enough cells in inducible state for tangible exogenous production has disinclined most laboratories from undertaking the venture. These laboratories turned instead to what appeared to be a more promising approach, a search for safe and effective interferogens. We, however, elected to produce interferon in vitro.The requirements for the production of interferon are simply stated: a supply of viable cells of the species desired; any interferogen to which these cells will respond, toxicity being of but little moment; methods for the isolation, concentration, and stabilization of the product; and a method for assay. We prepared interferon from L-929 mouse fibroblasts propagated in large-scale suspension culture systems. The inducer was live egg-grown Newcastle disease virus.

Interferon and murine leukemia. VII. Therapeutic effect of interferon preparations after diagnosis of lymphoma in akr mice

“…Graff, Kassel and their associates (Graff et al, 1970;Kassel, 1970) treated AKR mice with mouse interferon preparations of apparently much lower titer than those utilized in our experiments and reported regression of lymphadenopathy and an 8-fold increase in survival. We found no evidence of tumor regression in mice treated either with our more potent interferon preparations or with 20-fold diluted preparations.…”

“…We found no evidence of tumor regression in mice treated either with our more potent interferon preparations or with 20-fold diluted preparations. In this regard, it may be significant that the interferon used in the studies of Graff and his associates was reconstituted in horse serum (Graff et a/., 1970;Kassel, 1970) and Kassel and his associates have reported that " normal serum from a variety of species including the mouse, mimics the effects of interferon on AKR leukemia " (Kassel et a/., 1973). We therefore pose the question whether their results (Graff et al, 1970;Kassel, 1970) may not have been in part attributable to the presence of anti-leukemic factors derived from the horse serum (Kassel et al, 1973).…”

“…We have shown that interferon treatment of AKR mice for 1 year resulted in a reduction in the incidence of leukemia and a marked increase in mouse survival (Gresser et al, 19690). Graff, Kassel and their associates have reported that interferon preparations delayed the appearance of leukemia in AKR mice, and when injected into mice with " early to advanced leukemia " induced a reduction of lymphomatous tissues (Graff et al, 1970;Kassel, 1970;Kassel et a[., 1972) and a significant increase in survival (Graff et al, 1970;Kassel, 1970). The development of techniques for the production of large quantities of partially purified mouse interferon of high titer (Tovey et al, 1974) enabled us to determine the effect of considerably more potent interferon preparations than have previously been used on the survival of AKR mice after diagnosis of the lymphoma.…”

Production of Mouse Interferon with High Titers in a Large‐Scale Suspension Culture System1

“…Earlier, Cantell and Paucker [2] reported the production and release of mouse IF in L cells grown in suspension after induction with Newcastle disease virus (NDV), but the titer was very low. Later, there have been only a few reports [5,13] on the suspension culture system of mammalian cells for IF production except that of human leukocytes [6,16]. Graff et al [5] prepared.…”

“…Later, there have been only a few reports [5,13] on the suspension culture system of mammalian cells for IF production except that of human leukocytes [6,16]. Graff et al [5] prepared. NDV-induced IFfrom L-929 cells propagated in a relatively large-scale suspension system.…”