Yurkovetsky Zoya R, Kirkwood John M, Edington Howard D, Marrangoni Adele M, Velikokhatnaya Lyudmila, Winans Matthew T, Gorelik Elieser, Lokshin Anna E
University of Pittsburgh Cancer Institute, Pennsylvania 15213, USA.
Clin Cancer Res. 2007 Apr 15;13(8):2422-8. doi: 10.1158/1078-0432.CCR-06-1805.
Interferon (IFN)-alpha2b is the only Food and Drug Administration-approved treatment for operable high-risk melanoma that has been shown to significantly and durably prolong relapse-free survival (RFS) of patients with stage IIB-III melanoma. Development of reliable serum assays may contribute to the development of methods for earlier detection of melanoma and the selection of patients who may be most susceptible to current available interventions with IFNalpha.
A powerful high-throughput xMAP multiplex immunobead assay technology (Luminex Corp., Austin, TX) was used to simultaneously test 29 cytokines, chemokines, angiogenic as well as growth factors, and soluble receptors in the sera of 179 patients with high-risk melanoma and 378 healthy individuals.
Serum concentrations of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-8, IL-12p40, IL-13, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, IFNalpha, tumor necrosis factor (TNF)-alpha, epidermal growth factor, vascular endothelial growth factor (VEGF), and TNF receptor II were found to be significantly higher in patients with resected high-risk melanoma compared with healthy controls. Bayesian Network algorithm classification of the data offered 90% sensitivity at 98% specificity with 96.5% of melanoma patients distinguished from healthy individuals. IFN-alpha2b therapy resulted in a significant decrease of serum levels of immunosuppressive and tumor angiogenic/growth stimulatory factors (VEGF, epidermal growth factor, and hepatocyte growth factor) and increased levels of antiangiogenic IFN-gamma inducible protein 10 (IP-10) and IFN-alpha. Pretreatment levels of proinflammatory cytokines IL-1beta, IL-1alpha, IL-6, TNF-alpha, and chemokines MIP-1alpha and MIP-1beta were found to be significantly higher in the serum of patients with longer RFS values of 1 to 5 and >5 years when compared with patients with shorter RFS of <1 year.
These data show that multiplexed analysis of serum biomarkers is useful for the evaluation of prognostic markers of clinical outcome and potential predictive markers of response to IFN-alpha2b in patients with high-risk operable melanoma.
干扰素（IFN）-α2b是美国食品药品监督管理局批准的唯一用于可手术的高危黑色素瘤的治疗药物，已证实其能显著且持久地延长IIB-III期黑色素瘤患者的无复发生存期（RFS）。开发可靠的血清检测方法可能有助于开发早期检测黑色素瘤的方法，以及选择可能对目前可用的IFNα干预措施最敏感的患者。
采用强大的高通量xMAP多重免疫磁珠检测技术（Luminex公司，得克萨斯州奥斯汀），同时检测179例高危黑色素瘤患者和378例健康个体血清中的29种细胞因子、趋化因子、血管生成因子、生长因子和可溶性受体。
与健康对照组相比，切除的高危黑色素瘤患者血清中白细胞介素（IL）-1α、IL-1β、IL-6、IL-8、IL-12p40、IL-13、粒细胞集落刺激因子、单核细胞趋化蛋白1（MCP-1）、巨噬细胞炎性蛋白（MIP）-1α、MIP-1β、IFNα、肿瘤坏死因子（TNF）-α、表皮生长因子、血管内皮生长因子（VEGF）和TNF受体II的浓度显著升高。对数据进行贝叶斯网络算法分类，在特异性为98%时灵敏度为90%，96.5%的黑色素瘤患者可与健康个体区分开来。IFN-α2b治疗导致免疫抑制和肿瘤血管生成/生长刺激因子（VEGF、表皮生长因子和肝细胞生长因子）的血清水平显著降低，抗血管生成的IFN-γ诱导蛋白10（IP-10）和IFN-α水平升高。与RFS小于1年的患者相比，RFS为1至5年和大于5年的患者血清中促炎细胞因子IL-1β、IL-1α、IL-6、TNF-α以及趋化因子MIP-1α和MIP-1β的预处理水平显著更高。
这些数据表明，血清生物标志物的多重分析有助于评估高危可手术黑色素瘤患者的临床预后预后标志物以及对IFN-α2b反应的潜在预测标志物。
