Interferon-α-Induced Biologic Modifications in Patients with Chronic Myelogenous Leukemia

Abstract

Serum neopterin (Np), beta 2-microglobulin (beta 2-M), and 2',5'-adenylate (2',5'A) levels and intracellular 2',5'A and human Mx (Hu-Mx) protein synthesis were measured in 20-24 chronic myeloid leukemia patients before and during 1 year of IFN-alpha treatment and in a further 8-9 patients before and at the end of the first and second treatment weeks only. Univariate analysis showed that IFN-alpha increased Np and 2',5'A serum levels and intracellular concentrations of 2',5'A and Hu-Mx significantly from the end of the first week to month 12 of therapy. The biologic marker profiles were similar in cytogenetic responders and nonresponders, as well as in patients treated with IFN-alpha early (< 12 months from diagnosis) or late (after > 12 months standard chemotherapy). Further, there were no differences in the short-term (first 14 days) or long-term (during 12 month therapy) induction of the biologic markers irrespective of whether IFN-alpha 2a or IFN-alpha 2b was given. Because multivariate analysis revealed no significant interactions between cytogenetic response, time to treatment, and type of IFN-alpha used, increments in intracellular 2',5'A and Hu-Mx protein were similar at all study times for all factor combinations tested. Np levels varied significantly only during the first 14 therapy days; changes in serum 2',5'A were never statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Interferons and Their Stimulated Genes in the Tumor Microenvironment

“…MHC Class I proteins associate with β2-microglobulin, also an ISG, in the endoplasmic reticulum for transport to the cell surface; augmentation of β2-microglobulin has been identified in patients after IFN-α2 or IFN-β. 177, 178 Processing of potential antigenic peptides for loading onto class I molecules occurs in the proteasome whose three subunits (LMP-2, LMP-7, and LMP-10) together with Transporter for Processing (TAP) are all ISGs that can also be induced by IRF7. 179–182 Findings of increases in MHC Class II and other ISGs in vitro led to assessment of changes in monocyte cell-surface markers using treatment of patients with IFN-β with significantly increased monocytes positive for HLA-DQ.…”

Pegylated interferon-α2b treatment in melanoma patients: influence on amino acids, 5-hydroxyindolacetic acid and pteridine plasma concentrations

“…These enzymes are the rate-limiting steps in the biosynthesis of 5-HT, dopamine and noradrenaline, respectively [8]. Treatment with IFN-a is associated with an impressive and lasting increase in neopterin (NEOP) concentrations [7,9]. Theoretically, by shunting away precursors of BH (4) , this increased production of NEOP could lead to BH (4) deficiency, and thereby hamper the synthesis of 5-HT, dopamine and noradrenaline, which could cause psychiatric disturbance.…”

Gene Modulatory Effects, Pharmacokinetics, and Clinical Tolerance of Interferon-α1b: A Second Member of the Interferon-α Family

“…Induction of transcriptionally regulated IFN-stimulated gene products, identified in patients at a dose of 15,000 human antiviral units/m 2 of IFN-a1, was at a dose of at least 50-fold less than that which has been identified for IFN-a2. 17,32,33 These results, when combined with the findings in the earlier clinical trial of IFN-a1 and the tolerability and efficacy in hepatitis B and hepatitis C virus infections reported during studies in China, 17,18 confirm that IFN-a1 is biologically and therapeutically active and may be better tolerated. Increases in IFN-stimulated genes were defined at doses that were as low or lower than those commonly used with IFN-a2.…”

“…β 2 ‐Microglobulin, TRAIL, and neopterin levels remained elevated over baseline in two patients assessed after >1 year of daily treatment, suggesting continued gene modulatory effects of IFN‐ α 1b. Induction of transcriptionally regulated IFN‐stimulated gene products, identified in patients at a dose of 15,000 human antiviral units/m 2 of IFN‐ α 1, was at a dose of at least 50‐fold less than that which has been identified for IFN‐ α 2 17 , 32 , 33…”