title: Sequential therapy with recombinant interferons gamma and alpha in patients with unfavorable prognosis of chronic myelocytic leukemia: clinical responsiveness to recombinant IFN-alpha correlates with the degree of receptor down-regulation.
abstract: Natural and recombinant interferons (IFNs) have already demonstrated therapeutic efficacy, including cytogenetic remissions, in patients with chronic myelocytic leukemia (CML). We investigated at the level of ligand-receptor interaction the question whether heterogeneity of receptor number or affinity might contribute to primary or secondary treatment failures in CML. We therefore analyzed IFN-gamma and IFN-alpha receptor expression and regulation during treatment with recombinant IFN-gamma and IFN-alpha in 15 patients with advanced CML. We found no difference in number or affinity of constitutively expressed IFN-gamma receptors (mean 1,100) and, on average, a 30% reduction of IFN-alpha receptors (mean 750) on peripheral blood mononuclear cells (PBMNC) of patients with chronic or accelerated CML as compared to mature granulocytes and/or bone marrow cells of healthy controls, which express on average 1,050 and 1,100 IFN-gamma and IFN-alpha receptors, respectively. While IFN-gamma receptor expression on PBMNC is not influenced upon treatment with rIFN-gamma, there is a substantial downregulation of IFN-alpha receptors in the course of rIFN-alpha therapy. Our data also show a differential pattern of receptor downregulation between patients achieving complete hematologic remission (CHR) (4 out of 12) compared with patients with partial hematologic remission (PHR) and non-responders. We conclude that differences in IFN receptor number cannot explain primary or secondary treatment failures. However, the differential ligand induced downregulation of IFN-alpha receptors in patients achieving CHR compared to those with PHR or non-responders suggest a prospective value of IFN-alpha receptor determination.
authors.affiliation: Department of Medicine, University of Göttingen, FRG.
authors.forename: H H
authors.initials: HH
authors.lastname: Bartsch
authors.forename: K
authors.initials: K
authors.lastname: Pfizenmaier
authors.forename: A
authors.initials: A
authors.lastname: Hanusch
authors.forename: P
authors.initials: P
authors.lastname: Scheurich
authors.forename: U
authors.initials: U
authors.lastname: Ucer
authors.forename: G A
authors.initials: GA
authors.lastname: Nagel
mesh_terms: D000328:Adult; D000368:Aged; D002986:Clinical Trials as Topic; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011971:Receptors, Immunologic / Q000378:metabolism; D017471:Receptors, Interferon
chemical_list: D007370:Interferon Type I; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D007371:Interferon-gamma