doxifluridine
{{short description|Nucleoside analog prodrug}}
{{Infobox drug
| IUPAC_name = 1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-methyloxolan-2-yl]-5-fluoropyrimidine-2,4-dione
| image = Doxifluridine.svg
| width = 150px
| type =
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 3094-09-5
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = V1JK16Y2JP
| PubChem = 18343
| DrugBank = DB12947
| ChemSpiderID = 17322
| synonyms = Doxyfluridine; doxifluridine; 5'-deoxy-5-fluorouridine; 5'-deoxy-5'-fluorouridine; 5'-fluoro-5'-deoxyuridine; 5'-dFUrd; 5'-DFUR; Furtulon; Ro 21-9738
| C = 9
| H = 11
| F = 1
| N = 2
| O = 5
| StdInChI = 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
| StdInChIKey = ZWAOHEXOSAUJHY-ZIYNGMLESA-N
| smiles = C[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=C(C(=O)NC2=O)F)O)O
}}
Doxifluridine (5'-deoxy-5-fluorouridine) 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.{{Cite web | url = https://www.drugs.com/international/doxifluridine.html | title = Doxifluridine | publisher = drugs.com}} 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.
Biology
5-Fluorouracil (5-FU), the nucleobase of doxifluridine, is currently an FDA-approved antimetabolite.{{cite journal | vauthors = Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF | title = Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs | journal = Chemical Reviews | volume = 116 | issue = 23 | pages = 14379–14455 | date = December 2016 | pmid = 27960273 | pmc = 7717319 | doi = 10.1021/acs.chemrev.6b00209 }} 5-FU is normally administered intravenously to prevent its degradation by dihydropyrimidine dehydrogenase in the gut wall. Doxifluridine 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.{{cite journal | vauthors = Schöffski P | title = The modulated oral fluoropyrimidine prodrug S-1, and its use in gastrointestinal cancer and other solid tumors | journal = Anti-Cancer Drugs | volume = 15 | issue = 2 | pages = 85–106 | date = February 2004 | doi = 10.1097/00001813-200402000-00001 | pmid = 15075664 }}
Within a cell, pyrimidine nucleoside phosphorylase or thymidine phosphorylase can metabolize doxifluridine into 5-FU.{{cite journal | vauthors = Ishikawa T, Sekiguchi F, Fukase Y, Sawada N, Ishitsuka H | title = 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 | journal = Cancer Research | volume = 58 | issue = 4 | pages = 685–690 | date = February 1998 | pmid = 9485021 }}{{Cite web|url=https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=481255|title=Definition of Doxifluridine|publisher=National Cancer Institute|work=NCI Drug Dictionary}} It is also a metabolite of capecitabine. High levels of pyrimidine-nucleoside phosphorylase and thymidine phosphorylase are expressed in esophageal, breast, cervical, pancreatic, and hepatic cancers.{{cite journal | vauthors = 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 | display-authors = 6 | title = Expression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tumor tissues | journal = International Journal of Oncology | volume = 17 | issue = 1 | pages = 33–38 | date = July 2000 | pmid = 10853015 | doi = 10.3892/ijo.17.1.33 }}{{cite journal | vauthors = Ogata Y, Sasatomi T, Mori S, Matono K, Ishibashi N, Akagi Y, Fukushima T, Murakami H, Ushijima M, Shirouzu K | display-authors = 6 | title = Significance of thymidine phosphorylase in metronomic chemotherapy using CPT-11 and doxifluridine for advanced colorectal carcinoma | journal = Anticancer Research | volume = 27 | issue = 4C | pages = 2605–2611 | date = Jul 2007 | pmid = 17695422 }} 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.{{cite journal | vauthors = Lamont EB, Schilsky RL | title = The oral fluoropyrimidines in cancer chemotherapy | journal = Clinical Cancer Research | volume = 5 | issue = 9 | pages = 2289–2296 | date = September 1999 | pmid = 10499595 }}
The most frequent adverse effects for doxifluridine were neurotoxicity and mucositis.{{cn|date=February 2022}}
Brand names
Doxifluridine is sold under many brand names:{{Cite web|title=Medicine search - Doxifluridine|url=https://pillintrip.com/advanced_search?components=4462|access-date=2022-02-12|website=pillintrip.com}}
| class="wikitable"
!Brand name !Company !Country |
| Didox{{Cite journal| vauthors = Kim M, Ahn S, Son B, Lee J, Koh B, Sohn G, Lee S, Kim HJ |date=2017-02-23|title=Oncologic Effect of Oral Fluorouracil in Hormone Receptor-Negative T1a Node-Negative Breast Cancer Patients|url=http://www.koreamed.org/SearchBasic.php?RID=2368450|journal=Journal of Breast Disease|language=English|volume=4|issue=2|pages=116–121|doi=10.14449/jbd.2016.4.2.116 |issn=2288-5560|doi-access=free}}
|Shin Poong Pharm. Co., Ltd. | rowspan="3" |South Korea |
| Doxyfluridine
|Kwang Dong |
| Doxifluridine cap
|Myungmoon Pharma Co. Ltd. |
| Ai Feng
|Hengrui | rowspan="9" |China and Japan |
| Doxifluridine
|XinShiDai Pharmaceutical |
| Furtulon
|Roche, Chugai |
| Ke Fu
|Zhaohui |
| Ke Tuo
|Southwest |
| Qi Nuo Bi Tong
|Wanjie High-Tech |
| Shu Qi
|Team |
| Tan Nuo
|Xinchang Medicine & Chemical Co Ltd |
| Yi Di An
|Pacific |