Department of Surgery, Division of Surgical Oncology, UT Southwestern Medical Center, Dallas, TX, USA.
Ann Surg Oncol. 2010 May;17(5):1442-52. doi: 10.1245/s10434-009-0879-5. Epub 2009 Dec 30.
Pancreatic ductal adenocarcinoma (PDAC) frequently resists conventional cytotoxic therapy. The antitumor effects of endothelial monocyte-activating polypeptide II (EMAP) have been attributed to its antiendothelial and antiangiogenic activities. We tested the hypothesis that a combination of EMAP with bevacizumab (Bev) and gemcitabine (Gem) targets different pathways of PDAC progression and represents more effective treatment.
Proliferation of PDAC and endothelial cell lines was evaluated in vitro. In vivo tumor growth and survival PDAC xenograft experiments were performed with EMAP, Bev, and Gem, either alone or in combination. Intratumoral microvessel density and proliferative activity were analyzed by immunostaining with PECAM-1 and proliferating cell nuclear antigen antibodies, and apoptotic activity was measured by the TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) procedure.
Compared with controls, net reduction in tumor growth in EMAP, Bev, Gem, EMAP + Bev, EMAP + Gem, Bev + Gem, and EMAP + Bev + Gem groups was 58, 40, 40, 67, 68, 69, and 96%, respectively. Addition of EMAP to the Bev + Gem group statistically significantly improved survival at a median of >8 days while inducing long-term survival in some animals after maintenance therapy. Combination treatment of EMAP with Bev and Gem reduced proliferation of endothelial but not of PDAC cells. Addition of EMAP to Bev and Gem statistically significantly decreased proliferative activity while maintaining a comparable rate of microvessel density and apoptosis.
Addition of antiendothelial EMAP to a Bev and Gem regimen improves antitumor effects in a xenograft model of PDAC. This multitargeting strategy to prevent PDAC progression shows therapeutic promise and may overcome limitations by combinations of Gem with anti-vascular endothelial growth factor agents alone.
胰腺导管腺癌（PDAC）经常对常规细胞毒性治疗产生耐药性。内皮细胞单核细胞激活肽 II（EMAP）的抗肿瘤作用归因于其抗血管内皮和抗血管生成活性。我们检验了这样一个假设，即 EMAP 与贝伐单抗（Bev）和吉西他滨（Gem）联合应用可以靶向 PDAC 进展的不同途径，从而提供更有效的治疗。
在体外评估 PDAC 和内皮细胞系的增殖。通过 EMAP、Bev 和 Gem 单独或联合应用进行 PDAC 异种移植实验，以评估体内肿瘤生长和生存情况。通过 PECAM-1 和增殖细胞核抗原抗体的免疫染色分析肿瘤内微血管密度和增殖活性，并通过 TUNEL（末端脱氧核苷酸转移酶 dUTP 缺口末端标记）程序测量细胞凋亡活性。
与对照组相比，EMAP、Bev、Gem、EMAP+Bev、EMAP+Gem、Bev+Gem 和 EMAP+Bev+Gem 组肿瘤生长的净减少分别为 58%、40%、40%、67%、68%、69%和 96%。在 Bev+Gem 组中加入 EMAP 可使中位生存时间延长>8 天，而在维持治疗后一些动物中可诱导长期生存。EMAP 与 Bev 和 Gem 的联合治疗可减少内皮细胞而非 PDAC 细胞的增殖。与单独使用 Bev 和 Gem 相比，加入 EMAP 可显著降低增殖活性，同时保持微血管密度和凋亡的相似速率。
在 PDAC 的异种移植模型中，将抗血管内皮的 EMAP 加入 Bev 和 Gem 方案中可提高抗肿瘤效果。这种针对多种靶点的策略可防止 PDAC 进展，具有治疗潜力，并可能克服 Gem 与抗血管内皮生长因子药物联合应用的局限性。
