title: Gene modulatory effects, pharmacokinetics, and clinical tolerance of interferon-alpha1b: a second member of the interferon-alpha family.
abstract: Interferon-alpha1 (IFN-alpha1), which may have a primary role in innate immunity, differs significantly in amino-acid sequence from IFN-alpha2, the only recombinant IFN-alpha with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5-270 mug/m(2) of recombinant IFN-alpha1b. Gene modulation, pharmacokinetics, tolerability, and disease response were determined. Significant (P<0.01) dose and gene-dependent increases of 2-10 fold occurred in IFN-stimulated genes, including four (tumor necrosis factor-related apoptosis-inducing ligand, cig 5, p56, GEM) never previously identified as increased in patients; significant increases (P<0.01) resulted at the lowest dose (1.5 microg/m(2); 1.5 x 10(4) human antiviral units/m(2)). Increases (P<0.01) were sustainable for >4 weeks. Peak levels of IFN-alpha1b were at 3 h; an increase of approximately eightfold in both C(max) and AUC occurred between 15 microg/m(2) and 270 microg/m(2). Chronic toxicities of anorexia, weight loss, and fatigue were relatively uncommon. Eighteen patients were treated for >8 weeks; none experienced >grade 1 weight loss. Three patients at the highest dose developed grade 3 fatigue after > or =3 months, which required dose reduction or discontinuation. Patient acceptability of fatigue defined a dose for initiation of Phase II trials, 270 microg/m(2). Six patients (five with renal cell carcinoma) had progression-free survival for >1 year, including two who had partial responses. IFN-alpha1b resulted in potent stimulation of IFN-regulated genes and tumor regressions in renal cell carcinoma. Unique gene modulatory effects, when coupled with the moderate severity of side effects and a potentially central role in innate immunity, provide rationale for further clinical evaluation of IFN-alpha1 in virus infections and cancer.
authors.affiliation: Taussig Cancer Center, Center for Hematology and Oncology Molecular Therapeutics, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: P
authors.initials: P
authors.lastname: Masci
authors.forename: T
authors.initials: T
authors.lastname: Olencki
authors.forename: L
authors.initials: L
authors.lastname: Wood
authors.forename: L
authors.initials: L
authors.lastname: Rybicki
authors.forename: B
authors.initials: B
authors.lastname: Jacobs
authors.forename: B
authors.initials: B
authors.lastname: Williams
authors.forename: P
authors.initials: P
authors.lastname: Faber
authors.forename: R
authors.initials: R
authors.lastname: Bukowski
authors.forename: K
authors.initials: K
authors.lastname: Tong
authors.forename: E C
authors.initials: EC
authors.lastname: Borden
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001831:Body Temperature / Q000187:drug effects; D015331:Cohort Studies; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D019798:Neopterin / Q000096:biosynthesis; D010597:Pharmacogenetics; D016019:Survival Analysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis; D014452:Ubiquitins / Q000096:biosynthesis; D001613:beta 2-Microglobulin / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D016898:Interferon-alpha; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014452:Ubiquitins; D001613:beta 2-Microglobulin; C074034:ISG15 protein, human; D019798:Neopterin