Center for Hematology and Oncology Molecular Therapeutics, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
J Interferon Cytokine Res. 2011 May;31(5):433-40. doi: 10.1089/jir.2010.0054. Epub 2011 Jan 15.
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.
干扰素（IFN）-β在临床前研究中，与 IFN-α2 相比，与受体的结合亲和力更高，诱导产生更高水平的 IFN 刺激基因产物，诱导黑色素瘤细胞凋亡更多，并对黑色素瘤具有抗肿瘤作用。因此，在一项 IFN-β1a 治疗皮肤转移性黑色素瘤（n=17）和葡萄膜黑色素瘤（n=4）的 II 期临床试验中，使用了每周皮下注射 12×106 国际单位/m2，剂量递增至 18×106 国际单位/m2 的最大耐受剂量。这导致 21 例患者中有 13 例出现预期但可逆转的药物相关严重（3 级）不良事件；厌食和疲劳大多为轻度或中度严重程度，很少需要减少剂量。尽管有 1 例患者出现持续缓解，但 IFN-β1a 总体上没有临床获益（反应率<10%；中位无进展生存期 1.8 个月）。在周围血细胞和血清中有效和强效诱导产生 IFN 刺激基因产物，如促凋亡细胞因子 TRAIL 以及免疫调节和抗血管生成趋化因子 CXCL10 和 CCL8，证实了基因调节作用。为了进一步探究抗血管生成机制，评估了 VEGF-A 和 CXCL-5；与治疗前相比，这两种蛋白质都减少了。对抗肿瘤机制的理解不断提高，将增强 IFNs 对黑色素瘤淋巴结或远处转移的作用。
