title: VEGF secretion is inhibited by interferon-alpha in several melanoma cell lines.
abstract: Interferon-alpha (IFN-alpha) is employed in the treatment of malignant melanoma; however, it mediates regression of disease in only 10-15% of patients. Currently, its mechanism of action is uncharacterized. Low-dose IFN-alpha exerts anti-angiogenic effects when used in the treatment of life-threatening hemangiomas of infancy, suggesting anti-angiogenesis as a mechanism of action. IFN-alpha may exert its anti-tumor effect in the setting of advanced malignancy by inhibiting the secretion of vascular endothelial growth factor (VEGF), a pro-angiogenic substance. We hypothesized that IFN-alpha would decrease the release of VEGF by melanoma tumors. We studied the effect of IFN-alpha on VEGF production in nine human melanoma cell lines. We also examined VEGF levels in 49 patients with advanced malignancies who received low-dose IFN-alpha and interleukin-12 (IL-12) on an NCI-sponsored phase I trial. Human melanoma cell lines produced varying amounts of VEGF in vitro (60-1500 pg/mL at 48 h). Certain melanoma cell lines such as 18105 MEL secreted low levels of VEGF (152 pg/mL) after 48 h of culture, whereas other lines secreted very high levels (FO-1 3,802 pg/mL). Treatment of melanoma cells with IFN-alpha (2000 U/mL) decreased VEGF secretion by 40-60% in VEGF-high cell lines; however, this effect was not demonstrated in VEGF-low cell lines. In cancer patients, pretreatment VEGF plasma levels varied from 471 to 4200 pg/mL. A decrease in VEGF plasma levels after treatment directly correlated with the number of treatment cycles administered (Pearson correlation, p = 0.04). In summary, IFN-alpha inhibits VEGF secretion by melanoma cell lines in vitro and may have similar actions in malignancies that respond to IFN-alpha treatment.
authors.affiliation: Integrated Biomedical Sciences Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Ene T
authors.initials: ET
authors.lastname: Raig
authors.forename: Natalie B
authors.initials: NB
authors.lastname: Jones
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Varker
authors.forename: Kristen
authors.initials: K
authors.lastname: Benniger
authors.forename: Michael R
authors.initials: MR
authors.lastname: Go
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Biber
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D018664:Interleukin-12 / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D012878:Skin Neoplasms / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D018664:Interleukin-12
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