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The Oncologist, Vol. 3, No. 3, 198-203, June 1998
© 1998 AlphaMed Press

Physician Education

Gene Regulation and Clinical Roles for Interferons in Neoplastic Diseases

Ernest C. Borden

Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, USA

Correspondence: Ernest C. Borden, M.D., Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland 21201, USA. Telephone: 410-328-6825; Fax 410-328-7489.


   Overview
Top
 Overview
What Are IFNs?
 The IFN-{alpha} Receptor: A...
 Mechanisms of IFN-{alpha} Signal...
 Use of IFNs in...
 Conclusion
 References
 
Clinical indications for the use of interferons (IFNs) for cancer continue to expand and will likely continue to do so. IFNs have been approved for clinical use by the United States Food and Drug Administration for chronic myelogenous leukemia (CML), hairy cell leukemia, follicular lymphomas, Kaposi's sarcoma in the setting of AIDS, and melanoma for patients at high risk for recurrence after surgery. In addition, as a result of their antiviral activity, IFNs result in control of chronic active hepatitis and recurring papillomas that may reduce cancer development resulting from these processes and their underlying viruses. For almost all of these indications, therapeutic activity has been established from well-conducted, international phase III clinical trials.

IFNs were the first successful biological therapy for human malignancy; they can synergize to produce tumor regression with surgery and chemotherapy and can potentiate other cytokines and monoclonal antibodies. IFNs and cytokines can modulate gene expression, resulting in enhanced immune effector-cell number, cytotoxicity, antigen expression, and production of other cytokines. IFNs have pleiotropic effects on cellular function, including influences on growth, differentiation, and immunologic function (Table 1Go).


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  		Table 1. Some effects of interferons
 
For greatest effects, IFNs are used in combination with other modalities of therapy. This increases the effect of IFNs or allows IFNs to increase the effects of other therapies. Cytosine arabinoside improves the therapeutic effectiveness of IFNs in CML [1], and IFN-{alpha}2b improves the prognosis, survival, and quality of life after surgery for high-risk patients with melanoma [2]. Gene modulation by IFN-{alpha} or IFN-ß of thymidine phosphorylase, an enzyme important in DNA synthesis, has been suggested to be the basis for enhancing 5-fluorouracil (5-FU) effectiveness in preclinical models and may augment effectiveness in adenocarcinomas [3]. IFNs increase the expression of some tumor-associated antigens that could be of benefit for combination use with monoclonal antibodies for imaging or therapy [4, 5].


   What Are IFNs?
Top
 Overview
 What Are IFNs?
The IFN-{alpha} Receptor: A...
 Mechanisms of IFN-{alpha} Signal...
 Use of IFNs in...
 Conclusion
 References
 
IFN-{alpha} and IFN-ß are proteins produced in response to virus and to other specific stimuli for regulation of cell function (Fig. 1Go). They act, usually in a paracrine or endocrine manner, through high-affinity cell membrane receptors and signal transduction molecules to regulate gene expression. The biotechnology industry effectively harnessed the tools of recombinant DNA technology, discovered in academic laboratories, to produce these molecules as high-quality pharmaceuticals in quantity. Before the development and adaptation of recombinant DNA technology, less than a milligram of pure IFN had been isolated, so this biotechnological advance was particularly critical. Recombinant DNA technology also enabled more complete and precise definition of IFNs as a family of more than a dozen proteins (Table 2Go). IFNs have become the prototypic biological response modifier for the treatment of malignancies. In general, IFNs induce cellular effects of a pleiotropic nature in almost every tissue (Table 1Go); however, the individual IFNs may vary in their potency in mediating these biological effects. These differences almost certainly result in differing conformational interactions with their cognate receptors, conceivably further modified in a tissue-specific way (Fig. 2Go). As the IFN receptor complex has been defined, the rationale for further biological studies of differences in the IFN family has become stronger.



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  		Figure 1. Production of IFN-{alpha} or IFN-ß is stimulated by viruses through a final common pathway of double-stranded RNA or, in the case of IFN-{gamma}, exposure to specific antigens. Action of IFNs is mediated via binding to a specific receptor on the cell surface with induction of cell surface (HLA classes I and II, ß 2 microglobulin, tumor-associated antigens) and intracellular (2-5A synthetase, protein kinase, GTP cyclohydrolase, indoleamine dioxygenase, and other proteins of unidentified function) proteins that mediate biologic effects. Used with permission [39].

 

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  		Table 2. The IFN family. Type I IFNs include all forms of IFN-{alpha} and IFN-ß. Type II IFN is IFN-{gamma} only.
 



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  		Figure 2. Models for IFNs binding to their receptor and signal transduction initiation. A) IFNs bind to a two-component receptor which is dimerized by ligand binding. Tyrosines on activated receptor chains transfer phosphates to kinases which have become receptor-associated. B) IFNs- {alpha}, IFN-ß, and IFN-con1 bind to the same cell surface receptor, yet induce different cellular events. The diagram shows IFN-{alpha}8 binding more avidly to the receptor {alpha} chain, and IFN-{alpha}2 and IFN-ß binding more avidly to the receptor ß chain, but with different stearic interactions.

 

   The IFN-{alpha} Receptor: A Multi-Subunited Structure
Top
 Overview
 What Are IFNs?
 The IFN-{alpha} Receptor: A...
Mechanisms of IFN-{alpha} Signal...
 Use of IFNs in...
 Conclusion
 References
 
A critical step in receptor activation among members of the IFN receptor family is the ligand-dependent formation of a complex of receptor subunits (Fig. 2Go). JAK family kinases associated with the cytoplasmic domain of the receptor polypeptide chains activate the signaling process initiated by receptor oligomerization when the ligand binds [6, 7]. Two subunits of the IFN-{alpha} receptor have been identified, and both are located on human chromosome 21 [8]. Other studies suggest that more receptor components remain to be defined [9-11].

There are 500 to 2,000 high-affinity binding sites per human cell (Kd = 50 pM) [12]. Competitive binding studies have shown that IFN-con1, IFN-{alpha}8, and IFN-{alpha}2b bind similarly to the type-1 IFN-{alpha} receptor on human cells. With either the Daudi cells, B lymphoblastoid cells, or the CaKi renal carcinoma cell line, competitive binding experiments with 125I-IFN-con1 showed that IFN-con1 and IFN-{alpha}2b, as well as IFN-ß, bound the receptors with equal affinity [13]. In contrast, IFN-{alpha}8 competed poorly for binding, as did IFN-{alpha}7. When 125I-IFN was used in competitive binding studies with CaKi cells, IFN-{alpha}2b and IFN-con1 competed equally. These findings suggest that IFN-con1 and IFN-{alpha}2b bind to the type-1 receptor similarly. The number of binding sites recognized by IFN-con1 was consistently somewhat higher than other IFNs-{alpha} studied. Thus, IFNs may have different binding sites in the receptor, and IFN-con1 can bind with high efficiency to these different sites. However, the implication of this result for the biologic and biochemical activity of IFN-con1 is yet to be established.

For further information on the properties of the receptor for IFNs and the history of their discovery and characterization, the interested reader is referred to several reviews [14-17].


   Mechanisms of IFN-{alpha} Signal Transduction
Top
 Overview
 What Are IFNs?
 The IFN-{alpha} Receptor: A...
 Mechanisms of IFN-{alpha} Signal...
Use of IFNs in...
 Conclusion
 References
 
Studies on the mechanism of action of IFN have elucidated some of the potential biochemical bases for therapeutic effects and have aided in understanding the mechanisms of resistance. Knowledge of cellular regulatory processes and the genes controlling them will be helpful in identifying defects resulting in dysfunctional response and resistance to IFN. The JAK-STAT signal transduction pathway discovered from studies of mechanisms of molecular action of IFNs has proven to be part of the activation pathways for many cytokines. Cytokines that use the JAK-STAT signal transduction pathway activate unique combinations of JAK and STAT proteins. Which STAT protein is recruited to a specific receptor complex is determined by the specific interaction between the Stat peptide domains and the phosphotyrosine sites on the intracellular portion of the cytokine receptors.

Binding of an IFN to the cell-surface receptor initiates signals that are transmitted from the cell surface to the nucleus. The IFN receptor-associated JAK kinases transphosphorylate each other, and, in turn, phosphorylate tyrosine residues on the receptor chains (Fig. 3Go). The tyrosine residues on the receptor chains phosphorylated by the kinases become sites of association for the cytoplasmic STAT proteins. These are then phosphorylated by the JAK kinases associated with their intracytoplasmic receptors. As a result of this cascade of protein interactions, STAT1 and STAT2 form a heterodimer or a STAT1-STAT1 homodimer occurs (Fig. 3Go). The activated, phosphorylated STAT proteins move to the nucleus, complex with another protein, p48, which then interacts with enhancer elements upstream of the IFN-stimulated genes [18, 19]. The result of these signal transduction events initiated by receptor binding mediates expression of genes that mediate the pleiotropic biologic activities characteristic of IFNs [20, 21].



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  		Figure 3. The signal transduction pathway for IFNs. After binding to receptors, IFNs inititate gene activation through phosphorylation of intermediary proteins. The receptor-associated kinases, tyk2, JAK1 and JAK2, phosphorylate STAT1 and STAT2. After IFN-{alpha}, IFN-ß, or IFN-con1 bind to their common receptor, a heterodimer of STAT1 and STAT2 associates with another protein, p48, to form a complex which binds to a specific gene sequence. IFN-{gamma} binds a different receptor and activates STAT1, which, as a homodimer, activates a related but distinct nucleotide sequence resulting in transcription of different genes and synthesis of a different set of proteins. (Courtesy Daniel Lindner, M.D., Ph.D.)

 
Genes that are induced by IFNs are mostly quiescent or expressed at low levels. Their expression is regulated at the level of transcription in a rapid, transient process [22]. This effect is mediated through an enhancer DNA sequence termed the IFN-stimulated response element (ISRE), characterized by a conserved 15-base pair element [23, 24]. The ISRE has a consensus sequence GAAN(N)GAAA (N = any nucleotide) [18, 25, 26]. The ISRE is a necessary and sufficient component of the induction of many genes by IFN. An IFN-{gamma} activation site is composed of the consensus nucleotide sequence AANNNNNTT (N = any nucleotide), and confers responsiveness to IFN-{gamma} after binding of a STAT-1{alpha} homodimer [26].

Further information on signal transduction mechanisms and transcriptional factors that regulate gene expression by IFN-{alpha} may be found in recent reviews [20, 26, 27].


   Use of IFNs in the Treatment of Malignancy
Top
 Overview
 What Are IFNs?
 The IFN-{alpha} Receptor: A...
 Mechanisms of IFN-{alpha} Signal...
 Use of IFNs in...
Conclusion
 References
 
IFNs as single agents are active in inducing regressions in both hematologic malignancies and solid tumors (Table 3Go). Like many other agents, IFNs have had a higher overall response rate and quality-of-life impact for hematological malignancies than for solid tumors. The degree of activity and improvement in quality of life of patients with hairy cell leukemia resulted in the first licensed approval for an IFN in the United States. Decrease in bone marrow infiltration with malignant cells, as well as a normalization of peripheral hematologic variables resulted in reduced morbidity from the disease process [28]. Although other drugs now have proven active for this disease, IFN-{alpha} remains the treatment of choice in many European countries. In this brief article, data on hematologic malignancy (CML) and one solid tumor (melanoma) in which IFN-{alpha} has resulted in prolonged survival for patients treated at the appropriate disease stage will be reviewed.


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  		Table 3. Antitumor effectiveness of IFN-{alpha} in phase 2 or phase 3 clinical trials.
 
In CML, IFN-{alpha} results in a sustained therapeutic response in a majority (>75%) of patients with normalization of hematologic indices [29-32]. The equivalence and/or superiority of IFN-{alpha}2 to busulfan and hydroxyurea has been demonstrated [33-35]. An abnormal tyrosine kinase results from the chromosomal translocation abnormality which is the signature change underlying this disorder. The abnormal tyrosine kinase may protect the CML cells from physiological apoptotic cell death. A gradual reduction occurs in the frequency of cells bearing the underlying 9-22 chromosomal translocation because of therapy with IFNs. This reduction may take 12 to 24 months to be maximal. Up to 20% of patients will have a cytogenetic complete response with disappearance of uncontrolled cell proliferation resulting from the abnormal kinase. Median survival for patients who show some evidence of cytogenetic response, although not complete, is five to six years. Over 90% of cytogenetic complete responders can be expected to be in remission at 10 years. Interestingly, the MRC (Medical Research Council) [35] showed improved survival over chemotherapy for patients treated with IFN even in the absence of any cytogenetic response. Patients with sustained cytogenetic remissions may revert to PCR negativity and may help determine when IFN-{alpha}2 can be discontinued [36].

A potentially effective approach to enhancing the effectiveness of IFN-{alpha}2 for this disorder would be to combine it with a chemotherapeutic agent of differing mechanism of action. Studies exploring the addition of cytosine arabinoside in patients with later phases of CML seem to lead to longer remissions [31, 37]. This suggested that even greater impact might be achieved by use of IFN-{alpha}2 in newly diagnosed patients. A study of 721 patients confirmed this hypothesis, with significant evidence (p = 0.02) of prolonged survival in patients treated with the combination compared with patients treated with IFN-{alpha}2 alone [1]. A greater proportion of patients receiving the combination had a major or complete cytogenetic response (41% versus 24%, p < 0.01). Again, patients with major or complete cytogenetic response had longer survival whether or not they received cytosine arabinoside (p < 0.001). Although for patients with an eligible donor, allogeneic transplantation remains the only proven curative therapy. IFN-{alpha}2 has substantially altered the natural history of this disorder for the largest number of patients.

Objective regressions in metastatic melanoma in approximately 20% of patients treated with various doses and schedules provided rationale for trials using IFN-{alpha}2b to reduce recurrence rate in patients at risk for recurrence after surgery. Preclinical studies provided further rationale; immunomodulatory effects may be greater when tumor burden is reduced, and greater effectiveness in this setting has been demonstrated using IFN. Initial studies conducted in this patient population giving IFN-{alpha}2 for either short duration and/or for patients with <25% risk of recurrence failed to show any benefit. Potential study-design defects of either lack of sufficient dose intensity of IFN or enough statistical power to demonstrate a difference may have contributed to these negative results.

The only completed study using a dose-intensive approach in a high-risk group of patients had been that of ECOG [2]. In this multicenter trial, 52 weeks of therapy for patients with melanomas >4 mm of pathologic depth of invasion, or with lymph nodes histologically positive, resulted in increased median survival by >12 months and relapse-free survival by >9 months. Similarly, a 24% improvement in the five-year survival rate and a 42% improvement in the five-year relapse-free survival rate were observed. Although side effects leading to dose attenuation led to dose reduction in more than 50% of patients, 74% of patients were able to tolerate the full year of treatment at full or protocol-defined dose reductions. A second trial that was conducted to confirm these results and also to evaluate a lower dose given for a longer period of time will be mature in its duration of patient observation following treatment to ascertain differences in outcome with the next 12 months. However, another trial evaluating patients at lower risk has recently been reported which also suggests biological and clinical impact when IFN-{alpha}2b was given for minimal tumor burden [37].


   Conclusion
Top
 Overview
 What Are IFNs?
 The IFN-{alpha} Receptor: A...
 Mechanisms of IFN-{alpha} Signal...
 Use of IFNs in...
 Conclusion
References
 
IFNs led the way for successful application of human proteins for treatment of human neoplasia. IFNs differ from conventional systemic therapies for cancer in that they target expression of specific genes rather than DNA synthesis. Because of studies done over approximately two decades, we know which malignancies have the potential to respond therapeutically to IFNs, alone or in combination with other therapies. Cellular proteins, such as thymidine phosphorylase, protein kinase R, RNAase L, IRF transcription family proteins, and p21WAF1/CIP, which are modulated in expression by the IFN signal transduction pathway by IFNs, have the potential to influence the cell cycle and response to chemotherapeutic agents [22, 28]. Other induced genes such as MHC class I, GTP cyclohydrolase I, and carcinoembryonic antigen, can influence immunologic response. Thus, sequencing, timing, dose ratios, and duration of administration become important considerations. For clinical trial design, better definition of these molecular interactions will be increasingly critical.

To fully realize the potential of IFNs in oncology, further understanding of the mechanisms of antitumor action of the family of IFNs is required (Table 4Go). This should lead to understanding of the mechanisms underlying the troublesome chronic side effects, fatigue and anorexia. Improved clinical application of other effective cytokines in oncology will be facilitated, and expanded curative use of IFNs and growth factors or their agonists and antagonists for therapy of human malignancy will occur.


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  		Table 4. Translational research for more effective use of IFNs in cancer.
 


   References
Top
 Overview
 What Are IFNs?
 The IFN-{alpha} Receptor: A...
 Mechanisms of IFN-{alpha} Signal...
 Use of IFNs in...
 Conclusion
 References
 

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