Interferons

Ever since their discovery in 1957, the interferons seemed to offer advantages that would ensure their future as ideal antiviral agents. They are natural cellular products of viral infection and display a broad spectrum of activity against essentially all viruses (see Chapters 5, 7, and 8). Early clinical trials were conducted with inadequate amounts of semipurified interferons which had been produced by treating cultured human leukocytes or fibroblasts with a paramyxovirus or with a synthetic double-stranded RNA. However, in 1980 a major breakthrough was achieved when the gene for a human interferon a (IFN-a) was cloned and expressed in Escherichia coli. Since then, the genes for ail known subtypes of human IFN-a as well as I FN-(3 and IFN-y have been cloned in prokaryotic and/or eukaryotic cells. The yields so obtained are vastly greater than those from leukocyte, lymphoblastoid, or fibroblast cultures, and the cost of production has declined substantially.

Interferons are not effective by mouth, therefore are injected. IFN-a is much more active in vivo than IFN-p or IFN--y, probably because the latter do not achieve or maintain the required blood levels after intramuscular administration. Toxic side effects are regularly observed and may be marked with doses in excess of 107 units per day, even when highly purified cloned IFN subtypes are employed. Fever regularly occurs at high dosage but lasts only a day or so. Severe fatigue is the most debilitating symptom and may be accompanied by malaise, anorexia, myalgia, headache, nausea, vomiting, weight loss, erythema and tenderness at the injection site, partial alopecia (reversible), dry mouth, reversible peripheral sensory neuropathy, or signs referable to the centra] nervous system. Various indicators of myelosuppression (granulocytopenia, thrombocytopenia, and leukopenia) and abnormal liver function tests, both reversible on cessation of therapy, are regularly observed if high-dose interferon administration is prolonged.

Although the advent of less expensive interferons produced by recombinant DNA technology made it possible to treat patients with the sort of dosage that is required to produce clinically beneficial effects, it must be said that the successes are still rather modest. For example, some hepatitis C carriers respond to prolonged treatment with interferon a, but most relapse following withdrawal of the drug (Chapter 26). Genital warts have been successfully treated, and juvenile laryngeal papillomatosis, a severe condition calling for repeated surgical removal following recurrences, can be arrested by local injection of interferon; however, the tumors reappear when therapy is withdrawn (Chapter 18).

In the late 1970s reports of the partial regression of several types of cancers following interferon treatment precipitated a flurry of excitement, not only in cancer circles, but even on Wall Street, where the stocks of the newly emerging recombinant DNA based biotechnology companies skyrocketed overnight. However, subsequent more carefully controlled trials have given much less encouraging results. Only a minority of patients with only certain types of cancers, such as hairy cell leukemia and chronic myelocytic leukemia, respond favorably to vigorous interferon therapy, with temporary remission or partial regression. In these situations interferons may be acting not as antivirals but as cytokines exerting immunomodulatory effects. The euphoria of the late 1970s has been supplanted by a more cautious, balanced belief that interferons, while no panacea, may nevertheless come to occupy a limited place in both antiviral and anticancer chemotherapy. The future may lie in synergistic combinations of interferons with other types of antiviral or anticancer agents.

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