Journal
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH
Volume 28, Issue 9, Pages 553-561Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/jir.2008.0118
Keywords
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Funding
- National Institutes of Health [CA95426, 5P30 CA16058-28, K24 CA93670]
- The Melanoma Research Foundation [2-U01 CA-076576-06]
- The Valvano Foundation for Cancer Research Award
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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.
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