Centro de Pesquisas em Biologia Molecular e Funcional, Instituto Nacional de Ciência e Tecnologia em Tuberculose, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900 Porto Alegre, RS, Brazil.
Centro de Pesquisas em Biologia Molecular e Funcional, Instituto Nacional de Ciência e Tecnologia em Tuberculose, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900 Porto Alegre, RS, Brazil.
Biomed Pharmacother. 2021 Jul;139:111672. doi: 10.1016/j.biopha.2021.111672. Epub 2021 May 6.
Human thymidine phosphorylase (hTP) is overexpressed in several solid tumors and is commonly associated with aggressiveness and unfavorable prognosis. 6-(((1,3-Dihydroxypropan-2-yl)amino)methyl)-5-iodopyrimidine-2,4(1H,3H)-dione (CPBMF-223) is a noncompetitive hTP inhibitor, which has been described as a tumor angiogenesis inhibitor. The present study investigated the effects of CPBMF-223 in a xenograft tumor induced by human colorectal carcinoma cells (HCT-116). Additionally, CPBMF-223 capacity to reduce cell migration, its toxicological profile, and pharmacokinetic characteristics, were also evaluated. The intraperitoneal treatment with CPBMF-223 markedly prevented the relative tumor growth with an efficacy similar to that observed for 5-fluorouracil. Interestingly, number of vessels were significantly decreased in the treated groups. Moreover, CPBMF-223 significantly reduced the migration of cell line HCT-116. In the Ames assay and in an acute oral toxicity test, the molecule did not alter any evaluated parameter. Using the zebrafish toxicity model, cardiac and locomotor parameters were slightly changed. Regarding the pharmacokinetics profile, CPBMF-223 showed clearance of 9.42 L/h/kg after intravenous administration, oral bioavailability of 13.5%, and a half-life of 0.75 h. Our findings shed new light on the role of hTP in colorectal cancer induced by HCT-116 cell in mice, pointing out CPBMF-223 as, hopefully, a promising drug candidate.
人胸腺嘧啶磷酸化酶（hTP）在几种实体瘤中过表达，通常与侵袭性和不良预后相关。6-(((1,3-二羟基-2-丙基)氨基)甲基)-5-碘嘧啶-2,4(1H,3H)-二酮（CPBMF-223）是一种非竞争性 hTP 抑制剂，已被描述为肿瘤血管生成抑制剂。本研究探讨了 CPBMF-223 在人结直肠癌细胞（HCT-116）诱导的异种移植肿瘤中的作用。此外，还评估了 CPBMF-223 降低细胞迁移的能力、其毒理学特征和药代动力学特征。CPBMF-223 的腹腔治疗明显阻止了相对肿瘤生长，其疗效与 5-氟尿嘧啶相似。有趣的是，处理组的血管数量明显减少。此外，CPBMF-223 显著降低了细胞系 HCT-116 的迁移。在 Ames 试验和急性口服毒性试验中，该分子未改变任何评估参数。使用斑马鱼毒性模型，心脏和运动参数略有改变。关于药代动力学特征，CPBMF-223 静脉给药后清除率为 9.42 L/h/kg，口服生物利用度为 13.5%，半衰期为 0.75 h。我们的研究结果为 hTP 在 HCT-116 细胞诱导的结直肠癌中的作用提供了新的认识，并指出 CPBMF-223 有望成为一种有前途的候选药物。
