Tseng Jennifer F, Farnebo Filip A, Kisker Oliver, Becker Christian M, Kuo Calvin J, Folkman Judah, Mulligan Richard C
Department of Genetics, Harvard Medical School, and Division of Molecular Medicine, Children's Hospital, and Surgical Research Laboratories, Children's Hospital, Boston, Mass 02115, USA.
Surgery. 2002 Nov;132(5):857-65. doi: 10.1067/msy.2002.127680.
Because pancreatic adenocarcinoma is poorly responsive to chemotherapy and radiation therapy, novel treatments such as antiangiogenic gene therapy may have use in the adjuvant treatment of this malignancy. We evaluated the antitumor effects of the in vivo administration of an adenovirus vector encoding a soluble form of Flk1 (Flk1-Fc), a receptor for vascular endothelial growth factor, in 3 murine models of pancreatic adenocarcinoma.
In a first model, immunocompetent C57Bl/6 mice were injected subcutaneously with Panc02 murine pancreatic adenocarcinoma cells before treatment. In a second model, immunodeficient severe combined immunodeficiency mice were injected subcutaneously with BxPc-3 human pancreatic adenocarcinoma cells before treatment. In a third model, C57Bl/6 mice were injected with Panc02 cells through an intrasplenic route before treatment, in an effort to model metastatic disease. In each model, half the tumor-bearing mice were injected intravenously with 10(9) Flk1-Fc adenovirus particles and half with control adenovirus.
In subcutaneous tumor models, Ad Flk1-Fc-treated animals were found to have 75% smaller murine and 78% smaller human pancreatic tumor volumes, relative to tumor volumes of Ad Fc-treated animals, 6 weeks after vector administration. In animals injected with tumor through the intrasplenic route, pathologic and histologic analyses made 10 days after injection of tumor revealed hepatic, pancreatic, and splenic tumors, together with a desmoplastic response consistent with pathologic findings in human pancreatic cancer. Cohorts of these tumor-bearing mice treated with Ad Flk1-Fc demonstrated significantly longer survival and decreased liver replacement with tumor at the time of death, relative to animals treated with Ad Fc.
A recombinant adenovirus encoding soluble Flk-1 inhibited pancreatic tumor growth in mice. These studies suggest that the delivery of gene products such as Flk1-Fc through in vivo gene transfer may be useful in the future treatment of patients with pancreatic cancer.
由于胰腺腺癌对化疗和放疗反应不佳，诸如抗血管生成基因治疗等新疗法可能在这种恶性肿瘤的辅助治疗中发挥作用。我们在3种胰腺腺癌小鼠模型中评估了体内给予编码血管内皮生长因子受体Flk1可溶性形式（Flk1-Fc）的腺病毒载体的抗肿瘤效果。
在第一个模型中，免疫功能正常的C57Bl/6小鼠在治疗前皮下注射Panc02小鼠胰腺腺癌细胞。在第二个模型中，免疫缺陷的严重联合免疫缺陷小鼠在治疗前皮下注射BxPc-3人胰腺腺癌细胞。在第三个模型中，C57Bl/6小鼠在治疗前通过脾内途径注射Panc02细胞，以模拟转移性疾病。在每个模型中，一半荷瘤小鼠静脉注射10⁹个Flk1-Fc腺病毒颗粒，另一半注射对照腺病毒。
在皮下肿瘤模型中，给予载体6周后，发现Ad Flk1-Fc治疗的动物的小鼠胰腺肿瘤体积比Ad Fc治疗的动物小75%，人胰腺肿瘤体积小78%。在通过脾内途径注射肿瘤的动物中，注射肿瘤10天后进行的病理和组织学分析显示有肝、胰腺和脾脏肿瘤，以及与人类胰腺癌病理结果一致的促结缔组织增生反应。与Ad Fc治疗的动物相比，用Ad Flk1-Fc治疗的这些荷瘤小鼠队列显示存活时间显著延长，死亡时肿瘤对肝脏的替代减少。
一种编码可溶性Flk-1的重组腺病毒可抑制小鼠胰腺肿瘤生长。这些研究表明，通过体内基因转移递送诸如Flk1-Fc等基因产物可能在未来胰腺癌患者的治疗中有用。
