An antitumor prodrug of 5-fluorouracil
Doxifluridine(Ro 21-9738; 5'-DFUR) is a thymidine phosphorylase activator for PC9-DPE2 cells with IC50 of 0.62 μM. IC50 value: 0.62 μM(PC9-DPE2 cell).Target: Nucleoside antimetabolite/analogDoxifluridine is a fluoropyrimidine derivative and oral prodrug of the antineoplastic agent 5-fluorouracil (5-FU) with antitumor activity. Doxifluridine, designed to circumvent the rapid degradation of 5-FU by dihydropyrimidine dehydrogenase in the gut wall, is converted into 5-FU in the presence of pyrimidine nucleoside phosphorylase. 5-FU interferes with DNA synthesis and subsequent cell division by reducing normal thymidine production and interferes with RNA transcription by competing with uridine triphosphate for incorporation into the RNA strand.in vitro: 5'-DFUR's metabolic product(N3-Me-5'-dFUR) was found to be non-toxic in all the cell growth experiments performed. The absence of cytotoxicity could be explained by the observation that the metabolite was not recognized as a substrate by thymidine phosphorilase, the enzyme responsible for 5-fluorouracil (5-FU) release from doxifluridine, as ascertained by high-performance liquid chromatography/ultraviolet (HPLC-UV) analysis of the incubation mixture[1].in vivo: Administration of 200 mg of Furtulon to 23 beagle dogs, the plasma concentrations of doxifluridine, 5-FU, and 5-FUrd were measured simultaneously, using LC-MS/MS. The parent-metabolite compartment model with first-order absorption and Michaelis-Menten kinetics described the pharmacokinetics of doxifluridine, 5-FU, and 5-FUrd. Michaelis-Menten kinetics sufficiently explained the generation and elimination processes of 5-FU and 5-FUrd[2].Clinical trial: A phase II study of doxifluridine and docetaxel combination chemotherapy for advanced or recurrent gastric cancer was reported in 2009[3].
参考文献:
[1]. Dipartimento di Chimica, Università degli Studi della Basilicata, Potenza, In vitro toxicity of N3-methyl-5'-deoxy-5-fluorouridine, a novel metabolite of doxifluridine: a bioanalytical investigation. J Pharm Biomed Anal. 1998 May;17(1):11-6.
[2]. Baek IH, Lee BY, Kim MS, Pharmacokinetic analysis of doxifluridine and its metabolites, 5-fluorouracil and 5-fluorouridine, after oral administration in beagle dogs. Eur J Drug Metab Pharmacokinet. 2013 Apr 7.
[3]. Yoshikawa T, Tsuburaya A, Shimada K, A phase II study of doxifluridine and docetaxel combination chemotherapy for advanced or recurrent gastric cancer. Gastric Cancer. 2009;12(4):212-8.
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