title: Gene regulatory and clinical effects of interferon β in patients with metastatic melanoma: a phase II trial.
abstract: Interferon (IFN)-β in preclinical studies, compared to IFN-α2, bound with higher affinity to its receptor, induced to higher levels of IFN-stimulated gene products, induced more apoptosis in melanoma cells, and had antitumor effects against melanoma. A maximally tolerated dose of 12 × 10(6) international units/m(2) after 2 weeks subcutaneously daily with dose escalation to 18 × 10(6) international units/m(2) was thus used in a phase II trial of IFN-β1a in cutaneous metastatic melanoma (n = 17) and uveal melanoma (n = 4). It resulted in expected but reversible drug-related severe (grade 3) adverse events in 13/21 patients; anorexia and fatigue were mostly of mild or moderate severity and infrequently needed dose reduction. Although a single patient had a sustained regression, overall IFN-β1a did not have clinical benefit (response rate <10%; median progression-free survival 1.8 months). Effective and potent induction in peripheral blood cells and into serum of products of IFN-stimulated genes such as the pro-apoptotic cytokine, TRAIL, and the immunomodulatory and anti-angiogenic chemokines, CXCL10 and CCL8, confirmed gene regulatory actions. To probe further anti-angiogenic mechanisms, both VEGF-A and CXCL-5 were assessed; compared to before treatment, both proteins decreased. Continued improvements in understanding of antitumor mechanisms will enhance usefulness of IFNs for nodal or distant metastases from melanoma.
authors.affiliation: Center for Hematology and Oncology Molecular Therapeutics, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. bordene@ccf.org
authors.forename: Ernest C
authors.initials: EC
authors.lastname: Borden
authors.forename: Barbara
authors.initials: B
authors.lastname: Jacobs
authors.forename: Emese
authors.initials: E
authors.lastname: Hollovary
authors.forename: Lisa
authors.initials: L
authors.lastname: Rybicki
authors.forename: Paul
authors.initials: P
authors.lastname: Elson
authors.forename: Thomas
authors.initials: T
authors.lastname: Olencki
authors.forename: Pierre
authors.initials: P
authors.lastname: Triozzi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016899:Interferon-beta / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D016899:Interferon-beta