Interferons antitumor effects

The in vivo antitumor effects of interferons are believed to be related to both augmentation of natural killer cell activity and antiproliferative effects. Antiproliferative activity probably also accounts for the bone marrow suppression observed in some individuals given IFN and could potentially produce effects in a routine preclinical reproduction or teratology evaluation. Dosing studies performed in... 

This section describes the role of interferons as cancer drug therapies, emphasizing key contributions of recombinant biotechnology that made these therapeutic advances a reality. Additionally, some of the mechanisms by which the IFNs elicit antiproliferative or antitumor effects wiU be explored. 

Lindner, D.J., E.C. Borden, and D.V. Kalvakolanu, Synergistic antitumor effects of a combination of interferons and retinoic acid on human tumor cells in vitro and in vivo. Clin Cancer Res, 1997. 3(6) 931-7. 

Nomura, T., Yasuda, K., Yamada, T., et al. (1999). Gene expression and antitumor effects following direct interferon (IFN)-gamma gene transfer with naked plasmid DNA and DC-chol liposome complexes in mice. Gene Ther., 6(1), 121-129. 

Yoshida, J. et al. (2002). Antitumor effect of an adeno-associated virus vector containing the human interferon-beta gene on experimental intracranial human glioma. Jpn. J. Cancer Res. 93(2), 223-228. 

Kangas, L., Cantell, K. and Schellekens, H. (1990) Additive and synergistic antitumor effects with toremifene and interferons. Journal of Steroid Biochemistry, 36, 259—262. 

Antimicrob. Ag. Chemother. 17, 988 (1980). Mechanism of action study W. <3. Hearl, M. I. Johnston, Biochem. Bio-phys Res. Common. 138, 40 (1986). Antitumor effects in comparison wilh interferon H. R. Hubbell ei al, Cancer... 

In addition to antiviral effects, interferons have antitumor effects. The mechanisms of the antitumor effects are not well understood, but are probably likewise related to stimulation of specific gene expression by STAT proteins. Interferon-a, produced by recombinant DNA technology, has been used to treat patients such as Arlyn Foma who have certain types of nodular lymphomas and patients, such as Mannie Weitzels, who have chronic myelogenous leukemia. 

In the treatment of other diseases such as cutaneous T-cell lymphoma, ECP has shown an antitumor effect. The processing of the apoptotic lymphocytes by antigen-presenting cells induces a clonal cytotoxic response, which targets the malignant T-ceU population, process mediated by increased levels of TNE-a and interferon-gamma (IFN-y) produced by monocytes and lymphocytes after ECP. 

Natsume A, Mizuno M, Ryuke Y, Yoshida J. Antitumor effect and ceUular immunity activahon by murine interferon-beta gene transfer against intracerebral glioma in mouse. Gene Ther 1999 6 1626-1633. 

Interferons (lENs) (52,53), a family of species-specific vertebrate proteins, confer nonspecific resistance to a broad range of viral infections, affect cell proliferation, and modulate immune responses. AH three principal interferons, a-interferon (lEN-a) produced by blood leucocytes, P-interferon (lEN-P) by fibroblasts, and y-interferon (lEN-y) by lymphocytes, also have antiviral activity. The abiUty of interferons to inhibit growth of transplantable and carcinogen-induced tumor led to research showing the direct antiproliferative and indirect immune-mediated antitumor activities (see Chemotherapeutics, anticancer). IENs have been found to be efficacious in certain malignancies and viral infections, eg, hairy cell leukemia (85% response) and basal cell carcinoma (86% response). However, the interferons do have adverse side effects (54). 

Cytokines, eg, interferons, interleukins, tumor necrosis factor (TNF), and certain growth factors, could have antitumor activity directiy, or may modulate cellular mechanisms of antitumor activity (2). Cytokines may be used to influence the proliferation and differentiation of T-ceUs, B-ceUs, macrophage—monocyte, myeloid, or other hematopoietic cells. Alternatively, the induction of interferon release may represent an important approach for synthetic—medicinal chemistry, to search for effective antiinflammatory and antifibrotic agents. Inducers of interferon release may also be useful for lepromatous leprosy and chronic granulomatous disease. The potential cytokine and cytokine-related therapeutic approaches to treatment of disease are summarized in Table 4. A combination of cytokines is a feasible modaUty for treatment of immunologically related diseases however, there are dangers inherent in such an approach, as shown by the induction of lethal disserninated intravascular coagulation in mice adrninistered TNF-a and IFN-y. 

Interferon-a2b has diverse mechanisms of action, including antiviral activity, impact on cellular metabolism and differentiation, and antitumor activity.42 The antitumor activity is due to a combination of direct antiproliferative effect on tumor cells and indirect immune-mediated effects.42 Interferon-a2b is currently approved by the Food and Drug Administration (FDA) as adjuvant therapy for patients who are free of disease after curative surgical resection but are at high risk of MM recurrence. This includes patients with bulky disease or regional lymph node involvement such as stage IIB, IIC, or III disease.43 It is controversial if interferon-a2b (IFN) should be offered as adjuvant therapy for every high-risk MM patient. The reason is because clinical trials with different doses of IFN have not proved definitively that IFN improves overall patient survival. 

Interferon- gamma (INF-y) Antitumor Human (Phase I trial) Inhalation Inhalation increases alveolar concentration of INF-y without major side effects [99]... 

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