Scholz A, Wagner K, Welzel M, Remlinger F, Wiedenmann B, Siemeister G, Rosewicz S, Detjen K M
Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
Gut. 2009 Feb;58(2):261-70. doi: 10.1136/gut.2007.146415. Epub 2008 Oct 1.
Current systemic therapies for neuroendocrine tumours (NETs) do not provide sufficient control of tumour growth. However, efficient evaluation of novel drugs is hindered by the lack of a suitable preclinical animal model. Here an orthotopic mouse model of pancreatic NET is established and used to study the action of ZK 304709, a first in class, oral multitarget tumour growth inhibitor. ZK 304709 is an inhibitor of cyclin-dependent kinases (Cdks) 1, 2, 4, 7 and 9, vascular endothelial growth factor receptor-type kinases (VEGF-RTKs) 1-3 and platelet-derived growth factor receptor-type kinase beta (PDGF-RTKss).
BON and QGP-1 human NET cells were used to study proliferation, survival and cell cycle distribution in vitro. For induction of orthotopic NETs, BON cells were injected into the pancreas of NMRI(nu/nu) mice. Primary tumour growth and metastatic spread were recorded after 9 weeks, and apoptosis, microvessel density and lymphatic vessel density were determined.
ZK 304709 dose-dependently suppressed proliferation and colony formation of NET cells. Direct effects on NET cells were consistent with Cdk inhibition and involved G(2) cell cycle arrest and apoptosis induction, which was associated with reduced expression of MCL1 (myeloid cell leukaemia sequence 1), survivin and hypoxia-inducible factor 1alpha (HIF1alpha). Apoptosis similarly occurred in vivo in ZK 304709-treated orthotopic BON tumours, resulting in a 80% reduction of primary tumour growth. In contrast, treatment with lanreotide or 5-fluorouracil and streptozotocin failed to inhibit tumour gowth. ZK 304709 also reduced tumour microvessel density, implicating antiangiogenic mechanisms.
BON orthotopic tumours provide an informative model for preclinical drug evaluation in NETs. In this model, ZK 304709 achieved efficacious tumour growth control via induction of apoptosis and inhibition of tumour-induced angiogenesis.
目前用于神经内分泌肿瘤（NETs）的全身治疗无法充分控制肿瘤生长。然而，由于缺乏合适的临床前动物模型，新型药物的有效评估受到阻碍。在此，我们建立了胰腺NET的原位小鼠模型，并用于研究ZK 304709的作用，ZK 304709是一种新型的口服多靶点肿瘤生长抑制剂。ZK 304709是细胞周期蛋白依赖性激酶（Cdks）1、2、4、7和9、血管内皮生长因子受体型激酶（VEGF-RTKs）1 - 3以及血小板衍生生长因子受体型激酶β（PDGF-RTKss）的抑制剂。
使用BON和QGP - 1人NET细胞在体外研究增殖、存活及细胞周期分布。为诱导原位NETs，将BON细胞注射到NMRI（nu/nu）小鼠的胰腺中。9周后记录原发性肿瘤生长和转移扩散情况，并测定凋亡、微血管密度和淋巴管密度。
ZK 304709剂量依赖性地抑制NET细胞的增殖和集落形成。对NET细胞的直接作用与Cdk抑制一致，涉及G(2)期细胞周期停滞和凋亡诱导，这与MCL1（髓样细胞白血病序列1）、生存素和缺氧诱导因子1α（HIF1α）表达降低有关。在ZK 304709治疗的原位BON肿瘤体内同样发生凋亡，导致原发性肿瘤生长减少80%。相比之下，用兰瑞肽或5 - 氟尿嘧啶与链脲佐菌素治疗未能抑制肿瘤生长。ZK 304709还降低了肿瘤微血管密度，提示存在抗血管生成机制。
BON原位肿瘤为NETs临床前药物评估提供了一个有价值的模型。在该模型中，ZK 304709通过诱导凋亡和抑制肿瘤诱导的血管生成实现了有效的肿瘤生长控制。
