Interferons leukemia

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). 

DiaZepin Nucleosides. Four naturally occurring dia2epin nucleosides, coformycin (58), 2 -deoxycoformycin (59), adechlorin or 2 -chloro-2 -deoxycoformycin (60), and adecypenol (61), have been isolated (1—4,174,175). The biosynthesis of (59) and (60) have been reported to proceed from adenosine and C-1 of D-ribose (30,176,177). They are strong inhibitors of adenosine deaminase and AMP deaminase (178). Compound (58) protects adenosine and formycin (12) from deamination by adenosine deaminase. Advanced hairy cell leukemia has shown rapid response to (59) with or without a-or P-interferon treatment (179—187). In addition, (59) affects interleukin-2 production, receptor expression on human T-ceUs, DNA repair synthesis, immunosuppression, natural killer cell activity, and cytokine production (188—194). 

Agents which enhance the host s response against neoplasias or force them to differentiate are termed biological response modifiers. Examples include interleukin 2 which is used to treat renal cell carcinoma, interferon a which is active against hematologic neoplasias, and tretinoin (all-trans retinoic acid) which is a powerful inducer of differentiation in certain leukemia cells by acting on retinoid receptors. Side effects include influenza like symptoms, changes in blood pressure and edema. 

Interferon alfacon-1 (Inferax ), interferon alfa-2b (IntronA ), and interferon alfa-2a (Roferon -A) are applied in the treatment of chronic hepatitis B and C and some malignancies, especially hairy cell leukemia. IFN-a proteins induce the expression of antiviral, antiproliferative and immunomodulatory genes. 

Lymphosarcoma, severe psoriasis, cancer of the head, neck, breast, lung, rheumatoid arthritis (RA) Alpha-interferon-refractory hairy cell leukemia... 

Intron A interferon a-2b Schering-Plough Hairy cell leukemia, genital warts, AIDS-related Kaposi s sarcoma, hepatitis C, hepatitis B, malignant melanoma, follicular lymphoma in conjunction with chemotherapy... 

Golomb, H.M. et al., Report of a multi-institutional study of 193 patients with hairy cell leukemia treated with interferon-alfa2b, Semin, Oncol., 15, 7, 1988. 

Quesada, J.R. et al., Alpha interferon for induction of remission in hairy-cell leukemia, N. Engl. JMed., 310, 15, 1984. 

Teichmann, J.V. et al., Modulation of immune functions by long-term treatment with recombinant interferon-alpha 2 in a patient with hairy-cell leukemia, J Interferon Res, 8, 15, 1988. 

Alimena, G. et al., Interferon alpha-2b as therapy for Ph -positive chronic myelogenous leukemia A study of 82 patients treated with intermittent or daily administration, Blood, 72, 642, 1988. 

The Italian Cooperative Study Group on Chronic Myeloid Leukemia., Interferon alpha-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia, N. Engl. J. Med., 330, 820, 1994. 

Guilhot, F. et al., Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group, N. Engl. 

Interferon Immunomodulator antiviral, hairy cell leukemia Bone marrow suppression granulocytopenia leukopenia... 

Interferon- alpha-la 1986 and later Hairy cell leukemia, Kaposi s sarcoma... 

Interferons (IFN) are glycoproteins that, among other products, are released from virus-infected cells. In neighboring cells, interferon stimulates the production of "antiviral proteins." These inhibit the synthesis of viral proteins by (preferential) destruction of viral DNA or by suppressing its translation. Interferons are not directed against a specific virus, but have a broad spectrum of antiviral action that is, however, species-specific. Thus, interferon for use in humans must be obtained from cells of human origin, such as leukocytes (IFN-a), fibroblasts (IFN-P), or lymphocytes (IFN-y). Interferons are also used to treat certain malignancies and autoimmune disorders (e.g., IFN-a for chronic hepatitis C and hairy cell leukemia IFN-p for severe herpes virus infections and multiple sclerosis). 

Anstrom KJ, Reed SD, Allen AS, Glendenning GA, Schulman KA. Long-term snrvival estimates for ima-tinib versus interferon-alpha pins low-dose cytara-bine for patients with newly diagnosed chronic-phase chronic myeloid leukemia. Cancer 2004 101 2284-92. 

Interferon alfa-2b is useful in the treatment of a rare form of chronic leukemia, hairy cell leukemia, in which it produces remissions in 60 to 80% of patients. However, it has minimal antitumor activity in most human cancers. Remissions lasting a few months have been observed in 10 to 20% of patients with lymphomas, multiple myeloma, melanoma, renal cell carcinoma, and ovarian carcinoma. 

E. The discovery that the endogenous proteins known as interferons were capable of containing viral infections led to the hope that they would have many beneficial results, including anticancer activity. Although they are effective in the treatment of hairy cell leukemia and AIDS-associated Kaposi s sarcoma, they have not been shown to be the panacea that was originally envisioned. 

Hairy cell leukemia Interferon alfa-2a-. Subcutaneous, IM Initially, 3 million units/day for 16-24 wk. Maintenance 3 million units 3 times/wk. Do not use 36-million-unit vial. Interferon alfa-2b Subcutaneous, IM 2 million units/m 3 timesAvk. If severe adverse reactions occur, modify dose or temporarily discontinue. 

Chronic myelocytic leukemia (CML) Interferon alfa-2a-. Subcutaneous, IM 9 million units daily. 

Anionic polyelectrolytes have been shown to enhance resistance to bacteria and fungi, enhance immune response, inhibit adjuvent arthritis and either depress or stimulate phagocytic activity of the reticuloendothelial system [458,459]. Carboxylic acid polymers have shown interferon induction, antiviral activity, and tumor growth inhibition [460]. The effects include inhibition of sarcoma, leukemia, polyoma and vesicular stomatitis virus. In one application, the cytotoxicity of bleomycin toward cultured mammalian cells was synergisti-cally enhanced by stirring in the presence of high molecular weight polyfacrylic acid) [461]. 

Fig. 11.2. Domain structure of cytokine receptors. Schematic representation of the domain structure of selected cytokine receptors. WS motif conserved WSXWS sequence (W tryptophan S serine X non-conserved amino add) IL interleukin EpoR receptor for erythropoietin GHR growth hormone receptor LIF-R leukemia inhibitory factor receptor G-CSFR granulocyte colony stimulating factor receptor IFNR interferon receptor TNFR tumor necrosis factor receptor NGFR nerve growth factor receptor Fas, CD40 transmembrane receptors of lymphocytes.

Wiernik, P.H., B. Schwartz, J.P Dutcher, N. Turman, and C. Adinolfi, Successful treatment of hairy cell leukemia with beta-ser interferon. Am J Hematol, 1990. 33(4) 244-8. 

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