5-fluorodeoxyuridine

With the aid of cytosine permease, flucytosine reaches the fungal cell where it is converted by cytosine deaminase into 5-fluorouracil [51-21-8]. Cytosine deaminase is not present in the host, which explains the low toxicity of 5-FC. 5-Fluorouracil is then phosphorylated and incorporated into RNA and may also be converted into 5-fluorodeoxyuridine monophosphate, which is a potent and specific inhibitor of thymidylate synthetase. As a result, no more thymidine nucleotides are formed, which in turn leads to a disturbance of the DNA-synthesis. These effects produce an inhibition of the protein synthesis and cell repHcation (1,23,24). 5-Fluorouracil caimot be used as an antimycotic. It is poorly absorbed by the fungus to begin with and is also toxic for mammalian cells. 

Azathioprine, chloramphenicol, colchicine, cyclophosphamide, cytarabine, 5-fluorodeoxyuridine, 5-fluorouracil, hydroxyurea, mercaptopurine, metformin, methotrexate, phenobarbital, phenytoin, primidone, proton pump inhibitors, pyrimethamine, sulfasalazine, and vinblastine... 

Albumin. Albumin is available in highly pure and uniform form, and exhibits low toxicity and good biological stability. It has been used as a carrier for methotrexate and a variety of antiviral drugs [amantadine, fioxuridine (5-fluorodeoxyuridine), and cytar-abine (cytosine arabinoside)] to treat macrophage tumors and infections caused by DNA viruses growing in macrophages. Heavily modified albumins are known... 

Fig. 14.3 5 -FU catabolism, anabolism and mechanism of action. 5-FUH2, 5-fluoro-5,6-dihydrouracil 5-FdUMP, 5-fluorodeoxyuridine monophosphate TP, thymidine phosphorylase TK, thymidine kinase TS, thymidylate synthase CH2THF, 5,10-methylenetetrahydrofolate.

TK), 5-FU is activated to 5-fluorodeoxyuridine monophosphate (5-FdUMP). Potent inhibition of thymidylate synthase (TS) by 5-FdUMP is considered critical for 5-FU cytotoxicity. TS catalyzes the rate-limiting step of DNA synthesis, such as the conversion of dUMP into dTMP. Optimal TS function requires the formation of a covalent ternary complex consisting of TS, the folate cofactor 5,10-methylenetetra-hydrofolate (CH2THF), and 5-FdUMP. Inadequate cellular levels of 5,10-methyle-netetrahydrofolate reduce the stability of the ternary complex and consequently the inhibition of TS by 5-FdUMP. For this reason, 5-FU is administered in association with folinic acid, a precursor of 5,10-methylenetetrahydrofolate [40]. 

Fig. 14.10 Folate metabolism and role of MTHFR. Genetically reduced MTHFR activity affects the distribution between folate species required for protein and DNA synthesis. Higher availabil ity of 5,10-methylenetetrahydrofolate (CH2THF) potentiates the TS inhibition by 5-FdUMP, the active metabolite of 5-FU. Hey, homocysteine Met, methionine CH3HF, 5-methyltetrahydrofolate TS, thymidylate synthase 5-FdUMP, fluorodeoxyuridine monophosphate.

Berger SH, Jenh CH, Johnson LF, Berger FG. Thymidylate synthase overproduction and gene amplification in fluorodeoxyuridine-resistant human cells. Mol Pharmacol 1985 28 461 167. 

Koning, G.A., Morselt, H.W., Velinova, M.J., Donga, J., Gorter, A., Allen, T.M., Zalipsky, S., Kamps, J.A., and Scherphof, G.L. (1999) Selective transfer of a lipophilic prodrug of 5-fluorodeoxyuridine from immunoliposomes to colon cancer cells. Biochim. Biophys. Acta 1420(1-2), 153-167. 

Cattaneo-Pangrazzi RMC, et al. New amphiphilic heterodinucleoside phosphate dimers of 5-fluorodeoxyuridine (5FdUrd) cell cycle dependent cytotoxicity and induction of apoptosis in PC-3 prostate tumor cells. Biochem Pharmacol 2000 60 1887. 

Fig. 3. Metabolism of the fluoropyrimidines dTMP = deoxythymidine monophosphate, dUMP = deoxyuridine monophosphate, FdUDP = fluorodeoxyuridine diphosphate, FdUMP - fluoro-deoxyuridine monophosphate, FdUTP = fluorodeoxyuridine triphosphate, FU-DNA= fluorouracil-deoxyribonucleic acid, FUDP = fluorouracil diphosphate, FUMP = fluorouracil monophosphate, FU-RNA = fluorouracil-ribonucleic acid, FUTP = fluorouracil triphosphate.

Miller EM, Kinsella TJ. Radiosensitization by fluorodeoxyuridine Effects of thymidylate synthase inhibition and cell synchronization. Cancer Res 1992 52 1687-1694. 

Heimburger DK, Shewach DS, Lawrence TS. The effect of fluorodeoxyuridine on sublethal damage repair in human colon cancer cells, lnt J Radiat Oncol Biol Phys 1991 21 983-987. 

Lawrence TS, Davis M, Tang HY, et al. Fluorodeoxyuridine-mediated radiosensitization of human colon cancer cells is not caused by cell cycle redistribution. ProcAACR 1992 33 502, (abstr 3002). 

Thymidylate synthase (E.C. 2.1.1.45) is the enzyme that methylates UMP to thymidine, using methylene tetrahydrofolate as the carbon carrier. The enzyme can be inhibited directly by analogues of uracil such as 5-fluorouracil (8.34, 5-FU). The antimetabolite must be in the 5-fluorodeoxyuridine monophosphate (FdUMP) form to become active, and the capability of cells to achieve this transformation is a major determinant of their sensitivity to such drugs. 

Fig. 1. 5-FU metabolism. Abbreviations.- 5-FU (5-fluorouracil) FdUMP (fluorodeoxyuridine monophosphate) IS (thymidylate synthase) FUMP (fluorouridme monophosphate) DPD (dihydropyrimidine dehydrogenase) FUTP (fluorouridine triphosphate) FU H2 (dihydrofluorouracil) FBAL (fluoro-p-alanine).

Flucytosine is taken up by fungal cells via the enzyme cytosine permease. It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively (Figure 48-1). Human cells are unable to convert the parent drug to its active metabolites, resulting in selective toxicity. 

ALL, acute lymphoblastic leukemia AML, acute myelogenous leukemia CLL, chronic lymphocytic leukemia CML, chronic myelogenous leukemia DHFR, dihydrofolate reductase dNTP, deoxyribonucleotide triphosphate FdUTP, 5-fluorodeoxyuridine-5 -triphosphate FUTP, 5-fluorouridine-5 -triphosphate TS, thymidine synthase. 

Fluorouracil (5-FU) is inactive in its parent form and requires activation via a complex series of enzymatic reactions to ribosyl and deoxyribosyl nucleotide metabolites. One of these metabolites, 5-fluoro-2 -deoxyuridine-5 -monophosphate (FdUMP), forms a covalently ternary complex with the enzyme thymidylate synthase and the reduced folate 5,10-methylenetetrahydrofolate, a reaction critical for the de novo synthesis of thymidylate. This results in inhibition of DNA synthesis through "thymineless death." 5-FU is converted to 5-fluorouridine-5 -triphosphate (FUTP), which is then incorporated into RNA, where it interferes with RNA processing and mRNA translation. 5-FU is also converted to 5-fluorodeoxyuridine-5 -triphosphate (FdUTP), which can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function. Thus, the cytotoxicity of 5-FU is thought to be the result of combined effects on both DNA- and RNA-mediated events. 

Fluorouracil and fluorodeoxyuridine (floxuridine) inhibit pyrimidine nucleotide biosynthesis and interfere with the synthesis and actions of nucleic acids. To exert its effect, fluorouracil (5-FU)... 

Fluorouracil and fluorodeoxyuridine (floxuridine) inhibit pyrimidine nucleotide biosynthesis and interfere with the synthesis and actions of nucleic acids. To exert its effect, fluorouracil (5-FU) must first be converted to nucleotide derivatives such as 5-fluorodeoxyuridylate (5-FdUMP). Similarly, floxuridine (FUdR) is also converted to FdUMP by the following reactions ... 

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