Abma E, De Spiegelaere W, Vanderperren K, Stock E, Van Brantegem L, Cornelis I, Daminet S, Ni Y, Vynck M, Verstraete G, Smets P, de Rooster H
Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium.
Cancer Research Institute Ghent (CRIG), Medical Research Building, University Hospital Ghent, Ghent, Belgium.
Vet Comp Oncol. 2018 Dec;16(4):467-477. doi: 10.1111/vco.12402. Epub 2018 May 24.
Combretastatin A4-phosphate (CA4P) is an anti-tumour vascular targeting agent which selectively blocks tumour blood flow. Research on CA4P in rodent tumour models is extensive; however, knowledge of its effect on spontaneous cancer is scarce. This study was conducted in canine patients with spontaneous solid tumours. The goal was to assess the toxicity and efficacy of CA4P in various spontaneous tumour types. Eight dogs with spontaneous tumours were enrolled and treated with a single dose of 75 mg m intravenous CA4P. The dogs were screened and monitored before and after injection. Pre- and post-treatment tumour blood flow was analysed in vivo by power Doppler ultrasound (PDUS) and contrast-enhanced ultrasound (CEUS). Vessel destruction and tumour necrosis were evaluated by histopathology. Clinically relevant toxicity was limited to one case of temporary tetraparesis; other adverse events were mild. Significant cardiovascular changes were mostly confined to changes in heart rate and cTnI levels. Macroscopic tumour size reduction was evident in 2 dogs. Based on PDUS and CEUS, CA4P induced a significant decrease in vascular index and tumour blood flow. Post-treatment, histopathology revealed a significant increase of necrotic tumoural tissue and a significant reduction in microvessel density in tumoural tissue. Anti-vascular and necrotizing effects of CA4P were documented in a variety of canine spontaneous cancers with only minimal side effects. This is the first study reporting the administration of CA4P to canine cancer patients with in vivo and ex vivo assessment, and a first step toward implementing CA4P in combination therapies in veterinary oncology patients. The use of CA4P in canine patients was approved and registered by the Belgian Federal Agency for Medicines and Health Products (FAMHP) (approval number 0002588, registration number 6518 ID 2F12).
磷酸考布他汀A4（CA4P）是一种抗肿瘤血管靶向药物，可选择性阻断肿瘤血流。在啮齿动物肿瘤模型中对CA4P的研究广泛；然而，关于其对自发性癌症影响的了解却很少。本研究在患有自发性实体瘤的犬类患者中进行。目的是评估CA4P在各种自发性肿瘤类型中的毒性和疗效。八只患有自发性肿瘤的犬被纳入研究，接受单次静脉注射75mg/m的CA4P治疗。在注射前后对犬进行筛查和监测。通过功率多普勒超声（PDUS）和对比增强超声（CEUS）在体内分析治疗前和治疗后的肿瘤血流。通过组织病理学评估血管破坏和肿瘤坏死情况。临床相关毒性仅限于一例暂时性四肢轻瘫；其他不良事件较轻。显著的心血管变化主要局限于心率和肌钙蛋白I水平的变化。2只犬的肿瘤肉眼可见缩小。基于PDUS和CEUS，CA4P导致血管指数和肿瘤血流显著降低。治疗后，组织病理学显示坏死肿瘤组织显著增加，肿瘤组织中的微血管密度显著降低。CA4P的抗血管和坏死作用在多种犬自发性癌症中得到证实，且副作用极小。这是第一项报告对犬类癌症患者施用CA4P并进行体内和体外评估的研究，也是在兽医肿瘤学患者联合治疗中应用CA4P的第一步。CA4P在犬类患者中的使用已获得比利时联邦药品和健康产品局（FAMHP）的批准和注册（批准号0002588，注册号6518 ID 2F12）。
