MedKoo product information:

 Floxuridine

floxuridine is a fluorinated pyrimidine monophosphate analogue of 5-fluoro-2'-deoxyuridine-5'-phosphate (FUDR-MP) with antineoplastic activity. As an antimetabolite, floxuridine inhibits thymidylate synthetase, resulting in disruption of DNA synthesis and cytotoxicity. This agent is also metabolized to fluorouracil and other metabolites that can be incorporated into RNA and inhibit the utilization of preformed uracil in RNA synthesis. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

DRUG DESCRIPTION

Floxuridine for Injection USP, an antineoplastic antimetabolite, is available as a sterile, nonpyrogenic, lyophilized powder for reconstitution. Each vial contains 500 mg of floxuridine which is to be reconstituted with 5 mL of sterile water for injection. An appropriate amount of reconstituted solution is then diluted with a parenteral solution for intra-arterial infusion. Floxuridine is a fluorinated pyrimidine. Chemically, floxuridine is 2'-Deoxy-5-fluorouridine, with a molecular formula of C9H11FN2O5. It is a white to off-white odorless solid which is freely soluble in water. The 2% aqueous solution has a pH of between 4.0 and 5.5. The molecular weight of floxuridine is 246.20.

CLINICAL PHARMACOLOGY

When floxuridine is given by rapid intra-arterial injection it is apparently rapidly catabolized to 5-fluorouracil. Thus, rapid injection of floxuridine produces the same toxic and antimetabolic effects as does 5-fluorouracil. The primary effect is to interfere with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibit the formation of ribonucleic acid (RNA). However, when floxuridine is given by continuous intraarterial infusion its direct anabolism to floxuridine-monophosphate is enhanced, thus increasing the inhibition of DNA. Floxuridine is metabolized in the liver. The drug is excreted intact and as urea, fluorouracil, α-fluoro-β-ureidopropionic acid, dihydrofluorouracil, α-fluoro-β-guanidopropionic acid and α-fluoro-β-alanine in the urine; it is also expired as respiratory carbon dioxide. Pharmacokinetic data on intra-arterial infusion of floxuridine are not available.

 1: Sato A, Satake A, Hiramoto A, Okamatsu A, Nakama K, Kim HS, Wataya Y. Association of nuclear-intermediate filament lamin B1 with necrotic- and apoptotic-morphologies in cell death induced by 5-fluoro-2'-deoxyuridine. Nucleic Acids Symp Ser (Oxf). 2009;(53):293-4. PubMed PMID: 19749376.

2: Schott H, Schott S, Schwendener RA. Synthesis and in vitro activities of new anticancer duplex drugs linking 2'-deoxy-5-fluorouridine (5-FdU) with 3'-C-ethynylcytidine (ECyd) via a phosphodiester bonding. Bioorg Med Chem. 2009 Oct 1;17(19):6824-31. Epub 2009 Aug 21. PubMed PMID: 19744858.

3: Mocellin S, Pasquali S, Nitti D. Fluoropyrimidine-HAI (hepatic arterial infusion) versus systemic chemotherapy (SCT) for unresectable liver metastases from colorectal cancer. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD007823. Review. PubMed PMID: 19588444.

4: Galmarini CM, Warren G, Kohli E, Zeman A, Mitin A, Vinogradov SV. Polymeric nanogels containing the triphosphate form of cytotoxic nucleoside analogues show antitumor activity against breast and colorectal cancer cell lines. Mol Cancer Ther. 2008 Oct;7(10):3373-80. PubMed PMID: 18852140; PubMed Central PMCID: PMC2593126.

5: Sakurai Y, Yoshida I, Kamoshida S, Inaba K, Isogaki J, Komori Y, Uyama I, Tsutsumi Y. Changes of gene expression of thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase after the administration of 5'-deoxy-5-fluorouridine, paclitaxel and its combination in human gastric cancer xenografts. Anticancer Res. 2008 May-Jun;28(3A):1593-602. PubMed PMID: 18630517.

6: Sato A, Hiramoto A, Uchikubo Y, Miyazaki E, Satake A, Naito T, Hiraoka O, Miyake T, Kim HS, Wataya Y. Gene expression profiles of necrosis and apoptosis induced by 5-fluoro-2'-deoxyuridine. Genomics. 2008 Jul;92(1):9-17. PubMed PMID: 18572099.

7: Sato A, Hiramoto A, Satake A, Miyazaki E, Naito T, Wataya Y, Kim HS. Association of nuclear membrane protein lamin B1 with necrosis and apoptosis in cell death induced by 5-fluoro-2'-deoxyuridine. Nucleosides Nucleotides Nucleic Acids. 2008 May;27(5):433-8. PubMed PMID: 18569782.

8: Mocellin S, Pilati P, Lise M, Nitti D. Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: the end of an era? J Clin Oncol. 2007 Dec 10;25(35):5649-54. Review. PubMed PMID: 18065736.

9: Harasym TO, Tardi PG, Harasym NL, Harvie P, Johnstone SA, Mayer LD. Increased preclinical efficacy of irinotecan and floxuridine coencapsulated inside liposomes is associated with tumor delivery of synergistic drug ratios. Oncol Res. 2007;16(8):361-74. PubMed PMID: 17913044.

10: Ishizu K, Sunose N, Yamazaki K, Tsuruo T, Sadahiro S, Makuuchi H, Yamori T. Development and characterization of a model of liver metastasis using human colon cancer HCT-116 cells. Biol Pharm Bull. 2007 Sep;30(9):1779-83. PubMed PMID: 17827739.

11: Nishioka M, Miyamoto H, Kurita N, Higashijima J, Yoshikawa K, Miyatani T, Shimada M. Pyrimidine nucleoside phosphorylase and dihydropyrimidine dihydrogenase activities as predictive factors for the efficacy of doxifluridine together with mitomycin C as adjuvant chemotherapy in primary colorectal cancer. Hepatogastroenterology. 2007 Jun;54(76):1089-93. PubMed PMID: 17629045.

12: Matsuo R, Kondo T, Ohshiro Y, Moon Y, Yamamoto Y, Takeshima T, Todoroki T, Ohkohchi N. [A case of stage IVA intrahepatic biliary tract cancer successfully treated with gemcitabine]. Gan To Kagaku Ryoho. 2006 Oct;33(10):1501-4. Japanese. PubMed PMID: 17033247.

13: Mayer LD, Harasym TO, Tardi PG, Harasym NL, Shew CR, Johnstone SA, Ramsay EC, Bally MB, Janoff AS. Ratiometric dosing of anticancer drug combinations: controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice. Mol Cancer Ther. 2006 Jul;5(7):1854-63. PubMed PMID: 16891472.

14: Wang HE, Yu HM, Liu RS, Lin M, Gelovani JG, Hwang JJ, Wei HJ, Deng WP. Molecular imaging with 123I-FIAU, 18F-FUdR, 18F-FET, and 18F-FDG for monitoring herpes simplex virus type 1 thymidine kinase and ganciclovir prodrug activation gene therapy of cancer. J Nucl Med. 2006 Jul;47(7):1161-71. PubMed PMID: 16818951.

15: Temmink OH, de Bruin M, Laan AC, Turksma AW, Cricca S, Masterson AJ, Noordhuis P, Peters GJ. The role of thymidine phosphorylase and uridine phosphorylase in (fluoro)pyrimidine metabolism in peripheral blood mononuclear cells. Int J Biochem Cell Biol. 2006;38(10):1759-65. Epub 2006 May 9. PubMed PMID: 16798057.

16: Mizutani S, Oyama T, Hatanaka N, Uchikoshi F, Yoshidome K, Tori M, Ueshima S, Okuma K, Hiraoka K, Yamagami Y, Takahashi H, Sueyoshi K, Taira M, Nakahara M, Nakao K. [Combined chemotherapy with weekly Paclitaxel and doxifluridine for advanced and recurrent gastric cancers]. Gan To Kagaku Ryoho. 2006 Mar;33(3):327-31. Japanese. PubMed PMID: 16531712.

17: Shin HC, Kim JS, Vig BS, Song X, Drach JC, Amidon GL. Interaction of intestinal nucleoside transporter hCNT2 with amino acid ester prodrugs of floxuridine and 2-bromo-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole. Biol Pharm Bull. 2006 Feb;29(2):247-52. PubMed PMID: 16462026.

18: Seshimo A, Mitsuhashi M, Aratake K, Ogawa S, Itabashi M, Shirotani N, Kameoka S. [Prediction and treatment of peritoneal dissemination in gastric cancer]. Gan To Kagaku Ryoho. 2005 Oct;32(10):1393-7. Japanese. PubMed PMID: 16227736.

19: Kim I, Song X, Vig BS, Mittal S, Shin HC, Lorenzi PJ, Amidon GL. A novel nucleoside prodrug-activating enzyme: substrate specificity of biphenyl hydrolase-like protein. Mol Pharm. 2004 Mar-Apr;1(2):117-27. PubMed PMID: 15832508.

20: 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 Apr;4(4):659-67. PubMed PMID: 15827340.

21: Saiko P, Horvath Z, Jaeger W, Schott H, Fritzer-Szekeres M, Szekeres T. Heterodinucleoside phosphates of 5-fluorodeoxyuridine and arabinofuranosylcytosine--new drugs in cancer chemotherapy? In Vivo. 2005 Jan-Feb;19(1):205-14. Review. PubMed PMID: 15796176.

22: Megyeri A, Bacsó Z, Shields A, Eliason JF. Development of a stereological method to measure levels of fluoropyrimidine metabolizing enzymes in tumor sections using laser scanning cytometry. Cytometry A. 2005 Apr;64(2):62-71. PubMed PMID: 15729713.

23: Curbo S, Johansson M, Karlsson A. 5-Fluoro-2'-deoxyuridine has effects on mitochondria in CEM T-lymphoblast cells. Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1495-8. PubMed PMID: 15571284.

24: Emi Y, Kakeji Y, Baba H, Ishida T, Maehara Y. [Current combination chemotherapy containing paclitaxel for advanced, recurrent gastric cancer]. Gan To Kagaku Ryoho. 2004 Nov;31(12):1978-81. Review. Japanese. PubMed PMID: 15570924.

25: Otvös L, Sági G. [Antisense oligonucleotides with antitumor activity]. Magy Onkol. 2004;48(3):221-7. Epub 2004 Nov 1. Hungarian. PubMed PMID: 15520872.

26: Wang J, Yang M, Yagi S, Hoffman RM. Oral 5-FU is a more effective antimetastatic agent than UFT. Anticancer Res. 2004 May-Jun;24(3a):1353-60. PubMed PMID: 15274295.

27: Tabata T, Katoh M, Tokudome S, Hosakawa M, Chiba K, Nakajima M, Yokoi T. Bioactivation of capecitabine in human liver: involvement of the cytosolic enzyme on 5'-deoxy-5-fluorocytidine formation. Drug Metab Dispos. 2004 Jul;32(7):762-7. PubMed PMID: 15205393.

28: Zhang JM, Liu MJ, Mizoi T, Shiiba K, Sasak I, Matsuno S. [Thymidine phosphorylase expressed in monocyte-macrophages enhanced anticancer effect of 5'-deoxy-5-fluorouridine on colorectal carcinoma cells]. Zhonghua Yi Xue Za Zhi. 2004 May 2;84(9):718-24. Chinese. PubMed PMID: 15200906.

29: Casale F, Canaparo R, Serpe L, Muntoni E, Pepa CD, Costa M, Mairone L, Zara GP, Fornari G, Eandi M. Plasma concentrations of 5-fluorouracil and its metabolites in colon cancer patients. Pharmacol Res. 2004 Aug;50(2):173-9. PubMed PMID: 15177306.

30: Di Stefano G, Tubaro M, Lanza M, Boga C, Fiume L, Traldi P. Synthesis and physicochemical characteristics of a liver-targeted conjugate of fluorodeoxyuridine monophosphate with lactosaminated human albumin. Rapid Commun Mass Spectrom. 2003;17(22):2503-7. PubMed PMID: 14608620.

31: Yamaue H, Tanimura H, Kono N, Aoki Y, Tabuse K, Uchiyama K, Takifuji K, Iwahashi M, Tani M. Clinical efficacy of doxifluridine and correlation to in vitro sensitivity of anticancer drugs in patients with colorectal cancer. Anticancer Res. 2003 May-Jun;23(3B):2559-64. PubMed PMID: 12894541.

32: Takiguchi N, Ishii R, Koda K, Oda K, Miyazaki M. Thymidine phosphorylase expression correlates with malignant potential and anti-tumor effect of doxifluridine on gastric cancer: multivariate analysis for adjuvant chemotherapy doxifluridine vs. 5-fluorouracil. Oncol Rep. 2003 Sep-Oct;10(5):1105-11. PubMed PMID: 12883665.

33: Guo Y, Kotova E, Chen ZS, Lee K, Hopper-Borge E, Belinsky MG, Kruh GD. MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2',3'-dideoxycytidine and 9'-(2'-phosphonylmethoxyethyl)adenine. J Biol Chem. 2003 Aug 8;278(32):29509-14. Epub 2003 May 22. PubMed PMID: 12764137.

34: Yanagi Y, Tamaki Y, Inoue Y, Obata R, Muranaka K, Homma N. Subconjunctival doxifluridine administration suppresses rat choroidal neovascularization through activated thymidine phosphorylase. Invest Ophthalmol Vis Sci. 2003 Feb;44(2):751-4. PubMed PMID: 12556409.

35: Sato A, Shimada K, Nakamachi M, Ushio J, Yamamoto W, Kurihara M, Matsukawa M. Effectiveness of doxifluridine (5'-DFUR)/docetaxel against advanced/recurrent gastric cancer showing resistance to various anticancer drug regimens. Gastric Cancer. 2002;5(4):233-6. PubMed PMID: 12491082.

36: Grem JL, Danenberg KD, Kao V, Danenberg PV, Nguyen D. Biochemical and molecular effects of UCN-01 in combination with 5-fluorodeoxyuridine in A431 human epidermoid cancer cells. Anticancer Drugs. 2002 Mar;13(3):259-70. PubMed PMID: 11984070.

37: Kobayashi M, Wood PA, Hrushesky WJ. Circadian chemotherapy for gynecological and genitourinary cancers. Chronobiol Int. 2002 Jan;19(1):237-51. Review. PubMed PMID: 11962679.

38: Di Stefano G, Lanza M, Busi C, Barbieri L, Fiume L. Conjugates of nucleoside analogs with lactosaminated human albumin to selectively increase the drug levels in liver blood: requirements for a regional chemotherapy. J Pharmacol Exp Ther. 2002 May;301(2):638-42. PubMed PMID: 11961068.

39: Nagata T, Nakamori M, Iwahashi M, Yamaue H. Overexpression of pyrimidine nucleoside phosphorylase enhances the sensitivity to 5'-deoxy-5-fluorouridine in tumour cells in vitro and in vivo. Eur J Cancer. 2002 Mar;38(5):712-7. PubMed PMID: 11916555.

40: Matsushima H, Kawabe K, Fujime M, Kitamura T, Homma Y, Kishi H, Kawamura T, Umeda T, Ohishi Y, Murai M, Kawai T, Yoshida H, Fukuda T. Treatment of patients with superficial bladder cancer by intravesical instillation of anticancer drugs plus oral chemotherapy following TUR-Bt: a randomized controlled trial. Oncol Rep. 2002 Mar-Apr;9(2):283-8. PubMed PMID: 11836593.

41: Tobias SC, Borch RF. Synthesis and biological studies of novel nucleoside phosphoramidate prodrugs. J Med Chem. 2001 Dec 6;44(25):4475-80. PubMed PMID: 11728193.

42: Ferguson PJ, DeMoor JM, Vincent MD, Koropatnick J. Antisense-induced down-regulation of thymidylate synthase and enhanced cytotoxicity of 5-FUdR in 5-FUdR-resistant HeLa cells. Br J Pharmacol. 2001 Dec;134(7):1437-46. PubMed PMID: 11724749; PubMed Central PMCID: PMC1573083.

43: Takeda Y, Yoshizaki I, Nonaka Y, Yanagie H, Matsuzawa A, Eriguchi M. Docetaxel alone or orally combined with 5-fluorouracil and its derivatives: effects on mouse mammary tumor cell line MM2 in vitro and in vivo. Anticancer Drugs. 2001 Sep;12(8):691-8. PubMed PMID: 11604557.

44: Lin SB, Ts'o PO, Sun SK, Choo KB, Yang FY, Lim YP, Tsai HL, Au LC. Inhibition of thymidylate synthase activity by antisense oligodeoxynucleotide and possible role in thymineless treatment. Mol Pharmacol. 2001 Sep;60(3):474-9. PubMed PMID: 11502877.

45: Mata JF, García-Manteiga JM, Lostao MP, Fernández-Veledo S, Guillén-Gómez E, Larrayoz IM, Lloberas J, Casado FJ, Pastor-Anglada M. Role of the human concentrative nucleoside transporter (hCNT1) in the cytotoxic action of 5[Prime]-deoxy-5-fluorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug. Mol Pharmacol. 2001 Jun;59(6):1542-8. PubMed PMID: 11353816.

46: Fujimoto-Ouchi K, Tanaka Y, Tominaga T. Schedule dependency of antitumor activity in combination therapy with capecitabine/5'-deoxy-5-fluorouridine and docetaxel in breast cancer models. Clin Cancer Res. 2001 Apr;7(4):1079-86. PubMed PMID: 11309360.

47: Grem JL, Danenberg KD, Behan K, Parr A, Young L, Danenberg PV, Nguyen D, Drake J, Monks A, Allegra CJ. Thymidine kinase, thymidylate synthase, and dihydropyrimidine dehydrogenase profiles of cell lines of the National Cancer Institute's Anticancer Drug Screen. Clin Cancer Res. 2001 Apr;7(4):999-1009. PubMed PMID: 11309351.

48: Horikoshi N, Saotome T, Yoshida N, Aiba K. [Oral cancer chemotherapy in the clinic]. Gan To Kagaku Ryoho. 2000 Oct;27(11):1641-6. Review. Japanese. PubMed PMID: 11057313.

49: Kobayashi T, Kimura T. [Long-term outcome of preoperative chemotherapy with 5'-deoxy-5-fluorouridine (5'-DFUR) for gastric cancer]. Gan To Kagaku Ryoho. 2000 Sep;27(10):1521-6. Japanese. PubMed PMID: 11015996.

50: Ashour OM, Naguib FN, Goudgaon NM, Schinazi RF, el Kouni MH. Effect of administration of 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase, on the anti-tumor efficacy of 5-fluoro-2'-deoxyuridine against murine colon tumor C26-10. Biochem Pharmacol. 2000 Sep 1;60(5):687-92. PubMed PMID: 10927027.

51: Cattaneo-Pangrazzi RM, Schott H, Wunderli-Allenspach H, Rothen-Rutishauser B, Guenthert M, Schwendener RA. Cell-cycle arrest and p53-independent induction of apoptosis in vitro by the new anticancer drugs 5-FdUrd-P-FdCydOct and dCydPam-P-FdUrd in DU-145 human prostate cancer cells. J Cancer Res Clin Oncol. 2000 May;126(5):247-56. PubMed PMID: 10815759.

52: Britten C, Hammond L, Hidalgo M, Rothenberg ML, Sharma A, Sharma S, Siu L, Villalona-Calero M, Weiss GR. New anticancer agents. Cancer Chemother Biol Response Modif. 1999;18:178-209. Review. PubMed PMID: 10800483.

53: Xia Z, Wiebe LI, Miller GG, Knaus EE. Synthesis and biological evaluation of butanoate, retinoate, and bis(2,2,2-trichloroethyl)phosphate derivatives of 5-fluoro-2'-deoxyuridine and 2',5-difluoro-2'-deoxyuridine as potential dual action anticancer prodrugs. Arch Pharm (Weinheim). 1999 Aug;332(8):286-94. Review. PubMed PMID: 10489539.

54: Matsumoto S, Mashiba H, Okamoto K, Ekimoto H. [Evaluation of antitumor activity of etoposide administered orally for 21 consecutive days against human uterine cancer subcutaneous and/or orthotopic xenografts in nude mice]. Gan To Kagaku Ryoho. 1999 Aug;26(9):1313-20. Japanese. PubMed PMID: 10478185.

55: Yonekura K, Basaki Y, Chikahisa L, Okabe S, Hashimoto A, Miyadera K, Wierzba K, Yamada Y. UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin Cancer Res. 1999 Aug;5(8):2185-91. PubMed PMID: 10473104.

56: Evrard A, Cuq P, Ciccolini J, Vian L, Cano JP. Increased cytotoxicity and bystander effect of 5-fluorouracil and 5-deoxy-5-fluorouridine in human colorectal cancer cells transfected with thymidine phosphorylase. Br J Cancer. 1999 Aug;80(11):1726-33. PubMed PMID: 10468288; PubMed Central PMCID: PMC2363120.

57: Koning GA, Gorter A, Scherphof GL, Kamps JA. Antiproliferative effect of immunoliposomes containing 5-fluorodeoxyuridine-dipalmitate on colon cancer cells. Br J Cancer. 1999 Aug;80(11):1718-25. PubMed PMID: 10468287; PubMed Central PMCID: PMC2363118.

58: Koning GA, Morselt HW, Velinova MJ, Donga J, Gorter A, Allen TM, Zalipsky S, Kamps JA, Scherphof GL. Selective transfer of a lipophilic prodrug of 5-fluorodeoxyuridine from immunoliposomes to colon cancer cells. Biochim Biophys Acta. 1999 Aug 20;1420(1-2):153-67. PubMed PMID: 10446299.

59: Koizumi W, Saigenji K, Nakamaru N, Okayasu I, Kurihara M. Prediction of response to 5'-deoxy-5-fluorouridine (5'-DFUR) in patients with inoperable advanced gastric cancer by immunostaining of thymidine phosphorylase/platelet-derived endothelial cell growth factor. Oncology. 1999 Apr;56(3):215-22. PubMed PMID: 10202277.

60: Taguchi T. [Gastrointestinal cancer and oral anticancer agents]. Gan To Kagaku Ryoho. 1999 Feb;26(3):284-94. Review. Japanese. PubMed PMID: 10065090.

61: Wei Y, Yan Y, Pei D, Gong B. A photoactivated prodrug. Bioorg Med Chem Lett. 1998 Sep 22;8(18):2419-22. PubMed PMID: 9873553.

62: Ichikawa W, Osanai T, Shimizu C, Uetake H, Iida S, Yamashita T, Nishi N, Togo S, Miyanaga T, Nihei Z, Sugihara K. [Intra-arterial injection therapy of mitoxantrone for locally advanced breast cancer]. Gan To Kagaku Ryoho. 1998 Jul;25(9):1333-5. Japanese. PubMed PMID: 9703821.

63: Zambonin CG, Mastrolitti S, Palmisano F. Determination of N3-methyl-5'-deoxy-5-fluorouridine, a novel metabolite of doxifluridine, in body fluids by high performance liquid chromatography. J Pharm Biomed Anal. 1998 Jun;17(2):291-7. PubMed PMID: 9638582.

64: Zambonin CG, Aresta A, Grano M. 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. PubMed PMID: 9608421.

65: Fantz CR, Shaw D, Moore JG, Spencer HT. Retroviral coexpression of thymidylate synthase and dihydrofolate reductase confers fluoropyrimidine and antifolate resistance. Biochem Biophys Res Commun. 1998 Feb 4;243(1):6-12. PubMed PMID: 9473470.

66: Sachs MS, Selker EU, Lin B, Roberts CJ, Luo Z, Vaught-Alexander D, Margolin BS. Expression of herpes virus thymidine kinase in Neurospora crassa. Nucleic Acids Res. 1997 Jun 15;25(12):2389-95. PubMed PMID: 9171090; PubMed Central PMCID: PMC146768.

67: Tomoda H, Morita M, Matsuoka H, Baba H, Taketomi A, Kohnoe S, Seo Y, Saito T. [Pyrimidine nucleoside phosphorylase activity, 5-fluorouracil concentration and thymidylate synthase inhibition rate in colorectal cancer after oral administration of 5'-doxifluridine]. Gan To Kagaku Ryoho. 1997 Jun;24(8):971-4. Japanese. PubMed PMID: 9212806.

68: Akao S, Yoshida M, Abe S, Kojima M, Ishikawa H, Soma R. [The alteration of PyNPase activity in breast cancers due to preoperative oral administration of 5'-DFUR]. Gan To Kagaku Ryoho. 1997 Apr;24(6):685-90. Japanese. PubMed PMID: 9126305.

69: Kato Y, Matsukawa S, Muraoka R, Tanigawa N. Enhancement of drug sensitivity and a bystander effect in PC-9 cells transfected with a platelet-derived endothelial cell growth factor thymidine phosphorylase cDNA. Br J Cancer. 1997;75(4):506-11. PubMed PMID: 9052401; PubMed Central PMCID: PMC2063296.

70: Lévi F. [Chronopharmacology and chronotherapy of cancers]. Pathol Biol (Paris). 1996 Sep;44(7):631-44. Review. French. PubMed PMID: 8977920.

71: Zambonin CG, Palmisano F. Gas chromatography-mass spectrometry identification of a novel N3-methylated metabolite of 5'-deoxy-5-fluorouridine in plasma of cancer patients undergoing chemotherapy. J Pharm Biomed Anal. 1996 Aug;14(11):1521-8. PubMed PMID: 8877858.

72: Kurth S, Bulian D, Kreft B, Riemenschneider T. Intraarterial hepatic chemotherapy with fluorouracil, fluorodeoxyuridine, mitomycin C, cisplatin or methotrexate as single-agent anticancer drugs for a transplanted experimental liver tumor in rats. J Cancer Res Clin Oncol. 1996;122(7):421-6. Erratum in: J Cancer Res Clin Oncol 1997;123(3):187. PubMed PMID: 8690753.

73: Bjarnason GA. Clinical chronotolerance to anticancer drugs: relevance for dose-intensity. In Vivo. 1995 Nov-Dec;9(6):557-64. Review. PubMed PMID: 8726802.

74: Saito H, Okabe H, Nakano K, Fujioka A, Toko T, Takeda S, Unemi N. [Augmentation of chemotherapeutic efficaciousness of UFT by oral l-leucovorin--growth-inhibitory activity of combination against human tumor xenograft]. Gan To Kagaku Ryoho. 1995 Nov;22(13):1919-25. Japanese. PubMed PMID: 7487121.

75: Ogawa K, Miura K, Katsube T, Wagatsuma Y, Konno S, Wakasugi S, Watanabe T, Shimakawa T, Ishikawa S, Naritaka Y, et al. [Study on pyrimidine nucleoside phosphorylase (PyNPase) activity in resected tissues of patients with gastric cancer]. Gan To Kagaku Ryoho. 1995 Aug;22(9):1191-6. Japanese. PubMed PMID: 7661571.

76: Hrushesky WJ. Cancer chronotherapy: is there a right time in the day to treat? J Infus Chemother. 1995 Winter;5(1):38-43. Review. PubMed PMID: 7634176.

77: Lévi F. [Chrono-chemotherapy and dose intensity]. Bull Cancer. 1995;82 Suppl 1:29s-36s. French. PubMed PMID: 7626851.

78: Haruta A, Umeno T, Tanaka S, Toriya H, Jyozaki H, Ikeda S. [A study of preoperative administration of 5'-DFUR in patients with colo-rectal cancer]. Gan To Kagaku Ryoho. 1994 Oct;21(14):2427-30. Japanese. PubMed PMID: 7944487.

79: Vázquez-Padua MA. Modulation of thymidine kinase activity: a biochemical strategy to enhance the activation of antineoplastic drugs. P R Health Sci J. 1994 Mar;13(1):19-23. Review. PubMed PMID: 8016290.

80: Enigbokan MA, Preston J, Hubbard C, Thompson JO. Characterization of and the influence of calcium channel blockers on the renal excretion of pyrimidine anticancer agents. Res Commun Chem Pathol Pharmacol. 1994 Mar;83(3):270-8. PubMed PMID: 8008976.

81: van der Heyden S, Gheuens E, van de Vrie W, Van Bockstaele D, Van Oosterom A, Eggermont A, De Bruijn EA. 5'-Deoxy-5-fluorouridine increases daunorubicin uptake in multidrug-resistant cells and its activity is related with P-gp 170 expression. Jpn J Cancer Res. 1994 Jan;85(1):13-6. PubMed PMID: 7906263.

82: Laurent PL, Tevaearai HT, Eliason JF, Givel JC, Odartchenko N. Interferon alpha and 5'-deoxy-5-fluorouridine in colon cancer: effects as single agents and in combination on growth of xenograft tumours. Eur J Cancer. 1994;30A(12):1859-65. PubMed PMID: 7880618.

83: Haraguchi M, Furukawa T, Sumizawa T, Akiyama S. Sensitivity of human KB cells expressing platelet-derived endothelial cell growth factor to pyrimidine antimetabolites. Cancer Res. 1993 Dec 1;53(23):5680-2. PubMed PMID: 7694792.

84: Hrushesky WJ. Circadian pharmacodynamics of anticancer therapies. Clin Chem. 1993 Nov;39(11 Pt 2):2413-8. Review. PubMed PMID: 8222252.

85: Fisher TC, Milner AE, Gregory CD, Jackman AL, Aherne GW, Hartley JA, Dive C, Hickman JA. bcl-2 modulation of apoptosis induced by anticancer drugs: resistance to thymidylate stress is independent of classical resistance pathways. Cancer Res. 1993 Jul 15;53(14):3321-6. PubMed PMID: 8324744.

86: Henn TF, Garnett MC, Chhabra SR, Bycroft BW, Baldwin RW. Synthesis of 2'-deoxyuridine and 5-fluoro-2'-deoxyuridine derivatives and evaluation in antibody targeting studies. J Med Chem. 1993 May 28;36(11):1570-9. PubMed PMID: 8496926.

87: Funaki T, Onodera H, Ogawa K, Ichihara S, Fukazawa H, Kuruma I. Simultaneous determination of a new anticancer drug galocitabine and its metabolites in blood by high-performance liquid chromatography. J Pharm Biomed Anal. 1993 Apr-May;11(4-5):379-84. PubMed PMID: 8357875.

88: Yamashita Y, Takahashi M, Shinzato J, Bussaka H, Baba Y, Oguni T. Evaluation of oil-soluble FUdR ester for transcatheter arterial treatment of hepatomas. Ann Oncol. 1992 May;3(5):367-70. PubMed PMID: 1319732.

89: Barberi-Heyob M, Merlin JL, Webér B. Determination of 5-fluorouracil and its main metabolites in plasma by high-performance liquid chromatography. J Chromatogr. 1992 Jan 17;573(2):247-52. PubMed PMID: 1534812.

90: Machida H, Ashida N, Ikeda T, Sakata S, Baba M, Shigeta S. In vitro drug combination of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil with anti-human immunodeficiency virus or anticancer nucleosides. Antimicrob Agents Chemother. 1992 Jan;36(1):214-6. PubMed PMID: 1317147; PubMed Central PMCID: PMC189263.

91: Noda K, Ikeda M, Saito Y, Yajima A, Sato A, Suzuki M, Terashima Y, Ochiai K, Yoshida K, Takada M, et al. [Phase II study of 5'-DFUR in uterine cervical cancer and ovarian cancer]. Gan To Kagaku Ryoho. 1991 Dec;18(15):2557-65. Japanese. PubMed PMID: 1660700.

92: Maeda H, Miyamoto T, Mochinaga N, Tsunoda T. [5-Fluorouracil level and pyrimidine nucleoside phosphorylase activity in cancer patients after oral administration of doxifluridine (5'-DFUR)]. Gan To Kagaku Ryoho. 1991 May;18(6):965-9. Japanese. PubMed PMID: 1827573.

93: Goerlach A, Krauer KG, McKenzie IF, Pietersz GA. In vitro antitumor activity of 2'-deoxy-5-fluorouridine-monoclonal antibody conjugates. Bioconjug Chem. 1991 Mar-Apr;2(2):96-101. PubMed PMID: 1831049.

94: Naser-Hijazi B, Berger MR, Schmähl D, Schlag P, Hull WE. Locoregional administration of 5-fluoro-2'-deoxyuridine (FdUrd) in Novikoff hepatoma in the rat: effects of dose and infusion time on tumor growth and on FdUrd metabolite levels in tumor tissue as determined by 19F-NMR spectroscopy. J Cancer Res Clin Oncol. 1991;117(4):295-304. PubMed PMID: 1829730.

95: Bose S, Guha S, Paul P, Chowdhury M, Chowdhury SR, Sen U. The role of glutathione in evaluating the efficacy of antimetabolites in transplanted tumors. Neoplasma. 1991;38(2):193-8. PubMed PMID: 1828292.

96: Fukamura T, Umeno T, Jyozaki H, Haruta J, Okamoto K, Hashimoto M, Arima S, Shimura H. [Study of tissue drug concentration of fluorinated pyrimidine anticancer drugs--comparison of 5'DFUR and UFT]. Gan To Kagaku Ryoho. 1990 Sep;17(9):1887-92. Japanese. PubMed PMID: 2144106.

97: Yamashita Y, Takahashi M, Koga Y, Saito R, Nanakawa S, Hatanaka Y, Sato N, Nakashima K, Urata J, Yoshizumi K, et al. Prognostic factors in liver metastases after transcatheter arterial embolization or arterial infusion. Acta Radiol. 1990 May;31(3):269-74. PubMed PMID: 2167110.

98: Hrushesky WJ. Cancer chronotherapy: a drug delivery challenge. Prog Clin Biol Res. 1990;341A:1-10. PubMed PMID: 2145583.

99: Berry JP, Lespinats G, Escaig F, Boumati P, Tlouzeau S, Cavellier JF. Intracellular localization of drugs in cultured tumor cells by ion microscopy and image processing. Histochemistry. 1990;93(4):397-400. PubMed PMID: 2139017.

100: Shibata T, Sasaki Y, Imaoka S, Wada H, Nagano H, Ishikawa O, Ohigashi H, Fukuda I, Kabuto T, Hiratsuka M, et al. [Selective anticancer effects of intra-arterial infusion of 3',5'-dioctanoyl-5-fluoro-2'-deoxyuridine (TT82) in hepatocellular carcinoma]. Gan To Kagaku Ryoho. 1989 Aug;16(8 Pt 2):3057-61. Japanese. PubMed PMID: 2551246.

101: Iigo M, Nishikata K, Nakajima Y, Hoshi A, Okudaira N, Odagiri H, De Clercq E. Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5'-deoxy-5-fluorouridine against adenocarcinoma 755 in mice. Correlation with pharmacokinetics of plasma 5-fluorouracil levels. Biochem Pharmacol. 1989 Jun 15;38(12):1885-9. PubMed PMID: 2525905.

102: Nishiyama M, Takagami S, Kirihara Y, Saeki T, Hirabayashi N, Nosoh Y, Niimoto M, Hattori T. The antiproliferative effects of fluoropyrimidine derivatives against human tumor xenografts in a subrenal capsule assay. Jpn J Surg. 1988 Nov;18(6):725-8. PubMed PMID: 2977626.

103: Tsukagoshi S. [Problems in the development of analogs of anticancer drugs]. Gan To Kagaku Ryoho. 1988 Aug;15(8):2173-8. Japanese. PubMed PMID: 2457354.

104: Ajmera S, Bapat AR, Stephanian E, Danenberg PV. Synthesis and interaction with uridine phosphorylase of 5'-deoxy-4',5-difluorouridine, a new prodrug of 5-fluorouracil. J Med Chem. 1988 Jun;31(6):1094-8. PubMed PMID: 2967375.

105: Experimental and clinical studies on the anticancer agent, doxifluridine (5'-DFUR), Satellite symposium to the 25th annual meeting of the Japan Society for Cancer Therapy. Sapporo, Japan, 7 October 1987. Abstracts. J Int Med Res. 1988;16 Suppl 2:1B-39B. PubMed PMID: 2973421.

106: Scherphof GL, Daemen T, Spanjer HH, Roerdink FH. Liposomes in chemo- and immunotherapy of cancer. Lipids. 1987 Nov;22(11):891-6. PubMed PMID: 2965295.

107: Tsukagoshi S. [A new anticancer drug, 5'-deoxy-5-fluorouridine (5'-DFUR)]. Gan To Kagaku Ryoho. 1987 Oct;14(10):2977-82. Japanese. PubMed PMID: 2959207.

108: Au JL. Disposition and availability of 5-fluorouracil prodrug 5'-deoxy-5-fluorouridine after oral administration in rats. J Pharm Sci. 1987 Sep;76(9):699-702. PubMed PMID: 11002805.

109: Fujita F, Fujita M, Yamauchi T, Sakamoto Y, Shimozuma K, Inaba H, Taguchi T. [Effects of alternating chemotherapy with 2 non-cross-resistant drug combinations on human alimentary and breast cancer xenografts in nude mice]. Gan To Kagaku Ryoho. 1987 May;14(5 Pt 1):1297-304. Japanese. PubMed PMID: 2953311.

110: Fukushima S, Kawaguchi T, Nishida M, Juni K, Yamashita Y, Takahashi M, Nakano M. Selective anticancer effects of 3',5'-dioctanoyl-5-fluoro-2'-deoxyuridine, a lipophilic prodrug of 5-fluoro-2'-deoxyuridine, dissolved in an oily lymphographic agent on hepatic cancer of rabbits bearing VX-2 tumor. Cancer Res. 1987 Apr 1;47(7):1930-4. PubMed PMID: 3028618.

111: Fujita F, Fujita M, Hirai T, Taguchi T. [Evaluation by multiple regression analysis of factors influencing the chemosensitivity of human tumors xenografted into nude mice]. Gan To Kagaku Ryoho. 1987 Mar;14(3 Pt 1):618-25. Japanese. PubMed PMID: 2950823.

112: Roemeling RV, Hrushesky WJ. Circadian pattern of continuous FUDR infusion reduces toxicities. Prog Clin Biol Res. 1987;227B:357-73. PubMed PMID: 2957701.

113: Lin TS, Brubaker WF Jr, Wang ZH, Park S, Prusoff WH. Antineoplastic activity of 3'-(chloroethyl)nitrosourea analogues of 2'-deoxyuridine and 2'-deoxy-5-fluorouridine. J Med Chem. 1986 May;29(5):862-5. PubMed PMID: 2939245.

114: Nakagawa Y. [Pharmacokinetics of anticancer drugs in hamsters with tongue carcinoma]. Tsurumi Shigaku. 1986 May;12(2):259-76. Japanese. PubMed PMID: 2429415.

115: Irie K, Yasutake K, Imamura Y, Yoshimura Y, Yoshida M, Nakamura T, Suehiro I. [Clinical trial of 5'-deoxy-5-fluorouridine (5'-DFUR) in advanced cancer patients]. Gan To Kagaku Ryoho. 1985 Dec;12(12):2371-8. Japanese. PubMed PMID: 2934026.

116: Okumura T. [Clinical trial of 5'-DFUR against various malignant tumors]. Gan To Kagaku Ryoho. 1985 Dec;12(12):2365-70. Japanese. PubMed PMID: 2934025.

117: Fujimoto S, Shrestha RD, Igarashi K, Miyazaki M, Endoh F, Shimura T, Sugasawa H, Takahashi O, Kawata S, Ohta M, et al. [Anticancer treatment with a combination of antimetabolites of polyamine and pyrimidine]. Gan To Kagaku Ryoho. 1985 Oct;12(10):2024-9. Japanese. PubMed PMID: 2932057.

118: Schaaf LJ, Ferry DG, Hung CT, Perrier DG, Edwards IR. Analysis of 5'-deoxy-5-fluorouridine and 5-fluorouracil in human plasma and urine by high-performance liquid chromatography. J Chromatogr. 1985 Aug 9;342(2):303-13. PubMed PMID: 2932458.

119: Holl E, Zänker KS, Lange J, Siewert JR. On the differential affinities of two anticancer analogues to their target. Drugs Exp Clin Res. 1985;11(2):133-9. PubMed PMID: 2941256.

120: Fernandes DJ, Cranford SK. A method for the determination of total, free, and 5-fluorodeoxyuridylate-bound thymidylate synthase in cell extracts. Anal Biochem. 1984 Nov 1;142(2):378-85. PubMed PMID: 6241433.

121: Weiss GR, Garnick MB, Osteen RT, Steele GD Jr, Wilson RE, Schade D, Kaplan WD, Boxt LM, Kandarpa K, Mayer RJ, et al. Long-term hepatic arterial infusion of 5-fluorodeoxyuridine for liver metastases using an implantable infusion pump. J Clin Oncol. 1983 May;1(5):337-44. PubMed PMID: 6199474.

122: Suga S, Kimura K, Yokoyama Y, Isobe K, Yoshida Y, Takada T, Sato A, Kuwabara T, Iwase H. Studies on the designing of chemotherapy for gastric cancer in man, based on the tumor tissue concentration of anticancer agents. Gastroenterol Jpn. 1982;17(4):295-300. PubMed PMID: 6216137.

123: Goldman D, Bowen D, Gewirtz DA. Some considerations in the experimental approach to distinguishing between membrane transport and intracellular disposition of antineoplastic agents, with specific reference to fluorodeoxyuridine, actinomycin D, and methotrexate. Cancer Treat Rep. 1981;65 Suppl 3:43-56. Review. PubMed PMID: 6179615.

124: Tsukagoshi S. Overview of new anticancer drugs of interest in Japan. Cancer Treat Rev. 1980 Dec;7(4):215-24. PubMed PMID: 6452201.

125: Suzuki S, Hongu Y, Fukazawa H, Ichihara S, Shimizu H. Tissue distribution of 5'-deoxy-5-fluorouridine and derived 5-fluorouracil in tumor-bearing mice and rats. Gann. 1980 Apr;71(2):238-45. PubMed PMID: 6451469.

126: Boice JD, Greene MH, Keehn RJ, Higgins GA, Fraumeni JF Jr. Late effects of low-dose adjuvant chemotherapy in colorectal cancer. J Natl Cancer Inst. 1980 Mar;64(3):501-11. PubMed PMID: 6444445.

127: Hill DL, Montgomery JA. Selective uptake and retention of anticancer agents by sensitive cells. Cancer Chemother Pharmacol. 1980;4(4):221-5. Review. PubMed PMID: 6449312.

128: Miller EE, Ledis SL, Lo KW, Tsou KC. 5'-nucleotide phosphodiesterase activity of floxuridine-resistant mouse glioma. J Pharm Sci. 1976 Mar;65(3):384-7. PubMed PMID: 177749.

129: Brent RL, Bolden BT, Weiss A. The use of uterine vascular clamping in the pregnant rat to modify the embryotoxic effects of anticancer drugs. Cancer Res. 1968 Oct;28(10):2001-6. PubMed PMID: 4235148.