Floxuridine is an oncology drug classified as an antimetabolite and a specific inhibitor of thymidylate synthase[1]. Thymidylate synthase is the sole enzyme that catalyzes the de novo conversion of dUMP to dTMP, making it indispensable for DNA synthesis[2]. Floxuridine is usually used in antitumor and antiviral research[3].
In vitro, treatment of AsPC-1 pancreatic ductal cancer cells with Floxuridine (0.25–4mM; 2h) concentration-dependently inhibits cell proliferation and suppresses [³H]Gly-Sar uptake[4]. Treatment of OVCAR-8 ovarian cancer cells with Floxuridine (300μM; 24h) inhibits cell proliferation, induces the DNA-damage marker γ-H2AX, activates the ATM/ATR-Chk1/Chk2 checkpoint, and blocks cell G₁/S-phase recovery[5].
In vivo, Floxuridine (2.5mg/kg; single intraperitoneal injection) markedly inhibits multiple regulatory systems including Sae and Agr, induces prophages lysis, attenuates Staphylococcus aureus virulence, and raises the 7-day survival rate of mice from 0% to about 80% without altering blood glucose or blood cell counts in Staphylococcus aureus blood infects mice[6]. Floxuridine (2.5mg/kg; single intraperitoneal injection) significantly increased [¹⁸F]FLT uptake in various human tumor xenografted mouse models, including Ramos lymphoma, MDA-MB231 breast cancer, SKBR3 breast cancer, LS174T colon cancer, and WiDr colon cancer, with an average increase of 3.2–7.8 times[7].
References:
[1] Landowski CP, Vig BS, Song X, Amidon GL. Targeted delivery to PEPT1-overexpressing cells: acidic, basic, and secondary floxuridine amino acid ester prodrugs. Mol Cancer Ther. 2005;4(4):659-667.
[2] Ackland SP, Beale P, Peters GJ. Thymidylate synthase inhibitors. Cancer Chemother Biol Response Modif. 2003;21:1-28.
[3] Sato A, Hiramoto A, Kim HS, Wataya Y. Anticancer Strategy Targeting Cell Death Regulators: Switching the Mechanism of Anticancer Floxuridine-Induced Cell Death from Necrosis to Apoptosis. Int J Mol Sci. 2020;21(16):5876.
[4] Tsume Y, Hilfinger JM, Amidon GL. Enhanced cancer cell growth inhibition by dipeptide prodrugs of floxuridine: increased transporter affinity and metabolic stability. Mol Pharm. 2008;5(5):717-727.
[5] Huehls AM, Wagner JM, Huntoon CJ, et al. Poly(ADP-Ribose) polymerase inhibition synergizes with 5-fluorodeoxyuridine but not 5-fluorouracil in ovarian cancer cells. Cancer Res. 2011;71(14):4944-4954.
[6] Yeo WS, Arya R, Kim KK, Jeong H, Cho KH, Bae T. The FDA-approved anti-cancer drugs, streptozotocin and floxuridine, reduce the virulence of Staphylococcus aureus. Sci Rep. 2018;8(1):2521.
[7] Viertl D, Bischof Delaloye A, Lanz B, et al. Increase of [(18)F]FLT tumor uptake in vivo mediated by FdUrd: toward improving cell proliferation positron emission tomography. Mol Imaging Biol. 2011;13(2):321-331.
Floxuridine是一种抗代谢药物类抗癌药，是胸苷酸合酶的特异性抑制剂[1]。胸苷酸合酶是催化dUMP转化为dTMP的唯一酶，对DNA合成至关重要[2]。Floxuridine通常用于抗肿瘤和抗病毒研究[3][4]。
在体外，用Floxuridine（0.25–4mM；2小时）处理AsPC-1胰腺导管癌细胞可浓度依赖性地抑制细胞增殖并抑制[³H]Gly-Sar的摄取[5]。用Floxuridine（300μM；24小时）处理OVCAR-8卵巢癌细胞可抑制细胞增殖，诱导DNA损伤标志物γ-H2AX，激活ATM/ATR-Chk1/Chk2检查点，并阻断细胞从G₁/S期阻滞中恢复[2]。
在体内，Floxuridine（2.5mg/kg；单次腹腔注射）显著抑制Sae、Agr等多套毒力调控系统，诱导噬菌体裂解，降低金黄色葡萄球菌毒力，并使血液感染小鼠的7天存活率由0%升至约80%，且未引起血糖或血细胞计数变化[6]。Floxuridine（2.5mg/kg；单次腹腔注射）显著增加了多种人肿瘤异种移植小鼠模型（包括Ramos淋巴瘤、MDA-MB231乳腺癌、SKBR3乳腺癌、LS174T结肠癌和WiDr结肠癌）对[¹⁸F]FLT的摄取，平均增加了3.2–7.8倍[7]。