Interferon Alpha

Interferon-a-2a is produced by recombinant DNA technology-combining an Escherichia coli start codon with the DNA sequence for human interferon-a-2a. The resulting molecule is nearly identical to naturally occurring interferon-a, with the exceptions being the addition of an N-terminal methionine residue and the lack of carbohydrate side chains.18

This class of drugs, because of its antiproliferative and immunomodulatory capabilities, has found its place in the treatment of various malignancies. Specifically, interferon-a has exhibited clinical activity in multiple tumor types. Drug effect has been observed in acute and chronic leukemia, lymphomas, and multiple myeloma.20-23

The precise mechanism of action of interferons is not fully understood. Unlike traditional antineoplastic agents that exert their activity directly from their cyto-toxic interactions on cancer cells, interferon's benefits result from a complex cascade of biologic modulation and drug-induced antiproliferation. The binding of interferon to the cell surface elicits alterations in gene transcription and translation.24 Influences such as these on the activities of natural killer cells and macrophages appear to be the most noteworthy.25

Interferon's ability to inhibit cellular proliferation affects both normal and malignant cells. Although the mechanism is not completely understood, interferon-induced prolongation of the cell cycle is principally responsible for the antiproliferative effects.24 This activity appears to be concentration-dependent and occur primarily while the tumor cells are in phases G0 and G1.26 27 Additionally, these effects appear to be reversible since normal cellular growth resumes upon cessation of interferon exposure.24

Table 102.2 Therapeutic indications25

Drug

FDA approved indication

Interferon-a

Chronic myelogenous leukemia, condyloma acuminata, follicular lymphoma, hairy cell leukemia, chronic hepatitis B (adult and pediatric), chronic hepatitis C, Kaposi's sarcoma, malignant melanoma

Interferon-p

Multiple sclerosis

Interferon-^

Chronic granulomatous disease

Pharmacokinetics/metabolism

Interferon« is supplied as a clear liquid for injection. Bioavailability is greater than 80% upon subcutaneous or intramuscular injection.28 Interferon«, both recombinant and naturally occurring, is widely distributed in the body (excluding the central nervous system), with highest concentrations occurring in the spleen, kidney, liver, and lung.2428 The metabolism of recombinant interferon-a-2a is consistent with that of alpha interferons in general.24 Alpha-interferons undergo renal filtration and extensive proteolytic degradation at the brush border or in the lysosomes of the tubular epithelium during reabsorption, resulting in a half life of approximately 5 h.28 Because of the unique mechanism of metabolism, it has been suggested that interferon-a may accumulate in patients with impaired renal function, but this is con-troversial.24 Interferon-a may not be removed by hemodialysis.29

Toxicity

The side effect profile of interferon-a is well documented in the literature. Uniformly, with the first dose of interferon, patients experience a flu-like syndrome consisting of fever, chills/rigors, tachycardia, nausea, vomiting, malaise, and headaches.17'24 25 28 Although the presence of these side effects is relatively consistent, the severity can be affected by variables such as dose, route of administration, and treatment sched-ule.17 As a result of the cytokines released (IL-2, IL-6, TNF-a) in response to interferon administration, the patient's body attempts to generate heat via shivering and vasoconstriction. The onset of this fever, which often reaches 38-40°C, usually occurs within 4 h of drug administration and may persist for up to 8 h.1724 This reaction is frequently followed by a period of diaphoresis.25 As a preventative measure to attenuate this constellation of symptoms, patients may be pre-medicated with acetaminophen or nonsteroidal anti-inflammatory drugs. These symptoms will likely diminish over time and may resolve with continued therapy; however, tolerance may be lost if therapy is delayed for more than one day. 1724

On the other hand, fatigue continues and often worsens throughout therapy. Considered the most common dose-limiting toxicity, fatigue is often described as a feeling of lassitude, weakness, tiredness, or lack of motivation. This may manifest itself as job absenteeism, social withdrawal, increased sleeping, and potentially a decrease in performance status.172425 Intermittent and/or evening dosing schedules may diminish the impact of this significant side effect.2425 Laboratory abnormalities described with the use of interferon-a include neutropenia and elevated liver enzymes that require dose modifications to maintain safety. Other side effects include depression, myal-gias/arthralgias, gastrointestinal toxicity, and CNS depression.28

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