新型无环核苷酸类似物GS-343074和GS-424044在犬肿瘤细胞系中表现出抗增殖和促凋亡活性。
Novel acyclic nucleotide analogues GS-343074 and GS-424044 demonstrate antiproliferative and pro-apoptotic activity in canine neoplastic cell lines.
作者信息
Lawrence J A, Huelsmeyer M K, Thamm D H, Tumas D B, Birkus G, Kurzman I, Vail D M
机构信息
School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
出版信息
Vet Comp Oncol. 2015 Sep;13(3):246-54. doi: 10.1111/vco.12038. Epub 2013 May 15.
GS-9219, a novel prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine (PMEG) has significant activity as monotherapy in dogs with non-Hodgkin's lymphoma. Phase I trials have been initiated in humans based on the encouraging activity observed in canine lymphoma. Two new analogues of GS-9219 (GS-343074 and GS-424044) were recently produced for evaluation as potential novel antineoplastic agents against solid tumours. As a preclinical step, effect of GS-343074 and GS-424044 were evaluated against ten canine cancer cell lines for antiproliferative effect. Both analogues displayed antiproliferative activity against multiple canine cancer cell lines, although GS-343074 was more potent and of broader spectrum compared to GS-424044. Flow cytometric analysis of cells that experienced growth inhibition support apoptotic death as a mechanism of action for both analogues. On the basis of in vitro results described here, GS-343074 and GS-424044 show promise as novel anticancer agents in canine cancer.
GS-9219是核苷酸类似物9-(2-膦酰甲氧基乙基)鸟嘌呤（PMEG）的一种新型前药，在患有非霍奇金淋巴瘤的犬类中作为单一疗法具有显著活性。基于在犬类淋巴瘤中观察到的令人鼓舞的活性，已在人类中启动了I期试验。最近制备了两种GS-9219的新类似物（GS-343074和GS-424044），作为针对实体瘤的潜在新型抗肿瘤药物进行评估。作为临床前步骤，评估了GS-343074和GS-424044对十种犬癌细胞系的抗增殖作用。两种类似物均对多种犬癌细胞系显示出抗增殖活性，尽管与GS-424044相比，GS-343074效力更强且谱更广。对经历生长抑制的细胞进行的流式细胞术分析支持凋亡性死亡是两种类似物的作用机制。基于此处描述的体外结果，GS-343074和GS-424044在犬类癌症中作为新型抗癌药物显示出前景。
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