Doxifluridine

Doxifluridine
Clinical data
Other names	Doxyfluridine; 5'-Deoxy-5-fluorouridine; 5'-Fluoro-5'-deoxyuridine; 5'-dFUrd; 5'-DFUR
Identifiers
	IUPAC name 1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-methyloxolan-2-yl]-5-fluoropyrimidine-2,4-dione;
CAS Number	3094-09-5 ;
PubChem CID	18343;
ChemSpider	17322;
UNII	V1JK16Y2JP;
CompTox Dashboard (EPA)	DTXSID2022967 ;
ECHA InfoCard	100.019.491
Chemical and physical data
Formula	C9H11FN2O5
Molar mass	246.194 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=C(C(=O)NC2=O)F)O)O;
	InChI InChI=1S/C9H11FN2O5/c1-3-5(13)6(14)8(17-3)12-2-4(10)7(15)11-9(12)16/h2-3,5-6,8,13-14H,1H3,(H,11,15,16)/t3-,5-,6-,8-/m1/s1; Key:ZWAOHEXOSAUJHY-ZIYNGMLESA-N;

Doxifluridine is a second generation nucleoside analog prodrug developed by Roche and used as a cytostatic agent in chemotherapy in several Asian countries including China and South Korea.^[1] Doxifluridine is not FDA-approved for use in the USA. It is currently being evaluated in several clinical trials as a stand-alone or combination therapy treatment.

Generic names

5'-deoxy-5'-fluorouridine, 5'-deoxy-5-fluorouridine, 5'-DFUR, 5'-fluoro-5'-deoxyuridine, doxifluridine, doxyfluridine, Furtulon, Ro 21-9738

Biology

5-fluorouracil (5-FU) is currently an FDA-approved antimetabolite.^[2] 5-FU is normally administered intravenously to prevent its degradation by dihydropyrimidine dehydrogenase in the gut wall. Doxifluridine (5´-deoxy-5-fluorouridine) is a fluoropyrimidine derivative of 5-FU, thus a second-generation nucleoside prodrug. Doxifluridine was designed to improve oral bioavailability in order to avoid dihydropyrimidine dehydrogenase degradation in the digestive system.^[3]

Within a cell, pyrimidine nucleoside phosphorylase or thymidine phosphorylase can metabolize doxifluridine into 5-FU.^[4]^[5] It is also a metabolite of capecitabine.^[4] High levels of pyrimidine-nucleoside phosphorylase and thymidine phosphorylase are expressed in esophageal, breast, cervical, pancreatic, and hepatic cancers.^[6]^[7] Liberation of 5-FU is the active metabolite and leads to inhibition of DNA synthesis and cell death.

Side effects

High thymidine phosphorylase expression is also found in the human intestinal tract, resulting in dose-limiting toxicity (diarrhea) in some individuals.^[8]

The most frequent adverse effects for doxifluridine were neurotoxicity and mucositis.

Brand names

Ai Feng - Hengrui, China; Didox - Shin Poong, South Korea; Doxifluridine-XinShiDai Pharm - XinShiDai Pharmaceutical, China; Doxyfluridine Kwangdong - Kwang Dong, South Korea; Furtulon - Roche, China; Ke Fu - Zhaohui, China; Ke Tuo - Southwest, China; Qi Nuo Bi Tong - Wanjie High-Tech, China; Shu Qi - Team, China; Tan Nuo- Xinchang Medicine & Chemical Co Ltd, China; Yi Di An - Pacific, China; Doxifluridine cap- Myungmoon Pharma Co. Ltd.

References

^ "Doxifluridine". drugs.com.
^ Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF (Dec 2016). "Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs". Chem Rev. 116 (23): 14379–14455. doi:10.1021/acs.chemrev.6b00209. PMC 7717319. PMID 27960273.
^ Schöffski P (Feb 2004). "The modulated oral fluoropyrimidine prodrug S-1, and its use in gastrointestinal cancer and other solid tumors". Anticancer Drugs. 15 (2): 85–106. PMID 15075664.
^ ^a ^b Ishikawa, T; Sekiguchi, F; Fukase, Y; Sawada, N; Ishitsuka, H (1998). "Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts". Cancer Research. 58 (4): 685–90. PMID 9485021.
^ "Definition of Doxifluridine". NCI Drug Dictionary. National Cancer Institute.
^ Mori K, Hasegawa M, Nishida M, Toma H, Fukuda M, Kubota T, Nagasue N, Yamana H, Hirakawa-YS Chung K, Ikeda T, Takasaki K, Oka M, Kameyama M, Toi M, Fujii H, Kitamura M, Murai M, Sasaki H, Ozono S, Makuuchi H, Shimada Y, Onishi Y, Aoyagi S, Mizutani K, Ogawa M, Nakao A, Kinoshita H, Tono T, Imamoto H, Nakashima Y, Manabe T (Jul 2000). "Expression levels of thymidine phosphorylase and dihyropyrimidine dehydrogenase in various human tumor tissues". Int J Oncol. 17 (1): 33–8. doi:10.3892/ijo.17.1.33. PMID 10853015.
^ Ogata Y, Sasatomi T, Mori S, Matono K, Ishibashi N, Akagi Y, Fukushima T, Murakami H, Ushijima M, Shirouzu K (Jul 2007). "Significance of thymidine phosphorylase in metronomic chemotherapy using CPT-11 and doxifluridine for advanced colorectal carcinoma". Anticancer Res. 27 (4C): 2605–11. PMID 17695422.
^ Lamont EB, Schilsky RL (Sep 1999). "The oral fluoropyrimidies in cancer chemotherapy". Clin Cancer Res. 5 (9): 2289–96. PMID 10499595.

[1] "Doxifluridine". drugs.com.

[Shelton_2016-2] Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF (Dec 2016). "Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs". Chem Rev. 116 (23): 14379–14455. doi:10.1021/acs.chemrev.6b00209. PMC 7717319. PMID 27960273.

[Schöffski_2004-3] Schöffski P (Feb 2004). "The modulated oral fluoropyrimidine prodrug S-1, and its use in gastrointestinal cancer and other solid tumors". Anticancer Drugs. 15 (2): 85–106. PMID 15075664.

[Ishikawa-4] Ishikawa, T; Sekiguchi, F; Fukase, Y; Sawada, N; Ishitsuka, H (1998). "Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts". Cancer Research. 58 (4): 685–90. PMID 9485021.

[5] "Definition of Doxifluridine". NCI Drug Dictionary. National Cancer Institute.

[Mori_2000-6] Mori K, Hasegawa M, Nishida M, Toma H, Fukuda M, Kubota T, Nagasue N, Yamana H, Hirakawa-YS Chung K, Ikeda T, Takasaki K, Oka M, Kameyama M, Toi M, Fujii H, Kitamura M, Murai M, Sasaki H, Ozono S, Makuuchi H, Shimada Y, Onishi Y, Aoyagi S, Mizutani K, Ogawa M, Nakao A, Kinoshita H, Tono T, Imamoto H, Nakashima Y, Manabe T (Jul 2000). "Expression levels of thymidine phosphorylase and dihyropyrimidine dehydrogenase in various human tumor tissues". Int J Oncol. 17 (1): 33–8. doi:10.3892/ijo.17.1.33. PMID 10853015.

[Ogata_2007-7] Ogata Y, Sasatomi T, Mori S, Matono K, Ishibashi N, Akagi Y, Fukushima T, Murakami H, Ushijima M, Shirouzu K (Jul 2007). "Significance of thymidine phosphorylase in metronomic chemotherapy using CPT-11 and doxifluridine for advanced colorectal carcinoma". Anticancer Res. 27 (4C): 2605–11. PMID 17695422.

[Lamont_1999-8] Lamont EB, Schilsky RL (Sep 1999). "The oral fluoropyrimidies in cancer chemotherapy". Clin Cancer Res. 5 (9): 2289–96. PMID 10499595.

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