Interferon exerts anti-tumour effects in vitro and in vivo in animal experiments. It can also exert an anti-tumour effect on human neoplastic cells in vitro. This article summarizes the results obtained so far in the anti-tumour trials in man in Stockholm. The need for scaled-up production of human interferon is emphasized.
HuIFN-alpha has been found to consist of a family of 8-10 components. Their amino acid (165 and 166 residues) and nucleotide sequences are similar and also reveal some relationship to that of HuIFN-beta and even to those of murine alpha- and beta-interferons. It is thus likely that all mammalian interferons have originated from a common ancestral gene. Human beta- and some alpha-interferons have been obtained by genetic engineering in E.coli. All interferons seem to contain a relatively high proportion of hydrophobic amino acids and some of the components are glycosylated. The N-terminal residue of all HuIFN-alpha members is probably cysteine, that of the major HuIFN-beta peptide methionine and that of MuIFN-alpha and-beta probably alanine and isoleucine. Very little is known about the chemistry of any of the gamma-interferon species.
Potentiation of interferon action was described as a non-additive, synergistic enhancement of interferon activity by combined preparations of immune and virus-type interferons. The potentiated antiviral activity was demonstrated for a variety of virus types as well as for the human and mouse in vitro systems. Potentiation by combined immune and fibroblast interferons was also demonstrated for the antitumor and direct anticellular effects of interferon. Use of partially purified immune and fibroblast interferons demonstrated that potentiation appeared to be a property of the interferon molecules themselves.
The experimental data reviewed in this paper suggest that the inhibition of viral polypeptide chain initiation in IFN-treated cells involves the phosphorylation of eIF-2 alpha and intermediate factors (65K and 67K ribosomal proteins) by an IFN-induced dsRNA-dependent ribosomal kinase. However, the discrimination mechanism between viral and host cell mRNAs at the translational level remain to be elucidated, because the mechanism is very complex. IFN will induce, for example, preferential digestion of viral mRNAs by 2',5'-oligo A activated endoribonuclease, will impair tRNAs and elongation factors for the protein synthesis, and will decrease methylation of viral mRNAs, and they are involved in the discrimination mechanism at translational level. The activation of membrane-associated kinase activity by IFNs is very interesting because its among the earliest recognized biochemical events induced in cells and may play an important role in IFN-induced host or cell defense. Further studies focusing on the biochemical roles of the membrane-associated kinase in IFN-treated cells may provide evidence for understanding the biochemical mechanism of cell activation by IFNs.
Serum interferon is largely produced by B and T lymphocytes and macrophages, depending on the inducer. Lymphocyte interferon is different from macrophage and fibroblast interferon. There are two alleles controlling mouse interferon production. A protein possibly related to interferon may cause hyporeactivity. Our work was supported by NIH Grant 5-RO1-02953.
Both mouse and human cells elaborate more than one molecular species of interferon. Mouse interferon consists of a number of polypeptides which all probably have antiviral activity. Human fibroblast interferon is a single polypeptide, but other human cells produce special species of interferons, which show different physical and biological properties. The human interferons certainly differ in their extent of glycosylation and hydrophobicity, and may have different amino-acid sequences, since it has recently been reported that when the messenger RNAs extracted from fibroblast and lymphoblastoid cells are translated in Xenopus oocytes, the products are antigenically distinguishable (26,29,40). If the polypeptide sequences are different, then there may be at least two structural genes for human interferon. Both the antiviral and anticellular activities of mouse and human interferon probably reside in the same molecule.
Virus induced IFN (IFN alpha or beta) suppresses the antibody response in both mouse and human. The suppression may be related to IFN effect on intermediary metabolism (inhibition of hexose monophosphate shunt) which could result in activation of protein kinase activities. Immune IFN (IFN gamma) also suppresses the antibody response with purified IFN gamma more effective than crude, suggesting that crude IFN gamma preparations contain an antagonist. The cellular interactions that regulate IFN gamma production are similar to those for antibody production with helper and suppressor cell activities. T-cell growth factor or interleukin 2 will mediate helper cell requirements and appears to be an absolute requirement for IFN gamma production.
The clinical studies reviewed here indicated the usefulness of topical application of Human-fibroblast-derived (Beta) interferon (HulFN-B) in treatment of Adeno-8 Epidemic-keratoconjunctivitis. A week treatment with 2-5 X 10(5) reference units daily doses, starting early as possible, reduced the length of the disease from 22 day to a week, and almost totally prevented the appearance of subepithelial keratitis which occurred in 57% of the control group. Possibly interferon should be given also prophylactically to individuals exposed to contagion. Our results encourage further investigation on the Hul FN-B use as a drug for treatment and prevention of viral infection.
The studies reviewed here are encouraging in that HSV is moderately sensitive to the action of interferon and that infections in experimental animals clearly may be altered by exogenous interferon and interferon inducers. On the other hand it is apparent that the potential of this approach to treatment of herpesvirus infections is limited by the levels of interferon that can be passively administered or induced, the development of hyporeactivity which prevents maintaining high levels of interferon in infected animals after inoculation of inducers, and the failure to alter the course of HSV infection once the virus is established in target organs.
