Floxuridine

Last updated
Floxuridine
Floxuridine.png
Clinical data
AHFS/Drugs.com Monograph
MedlinePlus a682006
Routes of
administration 		Intra-arterial
ATC code
Identifiers
  • 5-Fluoro-1-[4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-1H-pyrimidine-2,4-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.066 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C9H11FN2O5
Molar mass 246.194 g·mol−1
3D model (JSmol)
Melting point 150.5 °C (302.9 °F)
  • FC=1C(=O)NC(=O)N(C=1)[C@@H]2O[C@@H]([C@@H](O)C2)CO
  • InChI=1S/C9H11FN2O5/c10-4-2-12(9(16)11-8(4)15)7-1-5(14)6(3-13)17-7/h2,5-7,13-14H,1,3H2,(H,11,15,16)/t5-,6+,7+/m0/s1 Yes check.svgY
  • Key:ODKNJVUHOIMIIZ-RRKCRQDMSA-N Yes check.svgY
   (verify)

Floxuridine (also 5-fluorodeoxyuridine) is an oncology drug that belongs to the class known as antimetabolites. Specifically, floxuridine is a pyrimidine analog, classified as a deoxyuridine. [1] The drug is usually administered via an artery, and most often used in the treatment of colorectal cancer. The quality of life and survival rates of individuals that receive continuous hepatic artery infusion of floxuridine for colorectal cancer metastases is significantly higher than control groups. [2] Floxuridine can also be prescribed for the treatment of kidney and stomach cancers. [3] In vitro uses of floxuridine include 5-minute treatments of fluorouracil, floxuridine, and mitomycin to increase cell proliferation in Tenon's capsule fibroblasts. [4]

Contents

Biosynthesis

Biosynthesis of floxuridine Floxuridine Biosynthesis.png
Biosynthesis of floxuridine

Immobilized Aeromonas salmonicida ATCC 27013, when exposed to thymidine and 5-fluorouracil in phosphate buffer at room temperature for one hour, can synthesize floxuridine and thymine. [5]

Pharmacology

Floxuridine primarily works by stopping the growth of newly born cells. [6] The drug essentially stops DNA from forming in new and rapidly developing cells, which is a sign of a cancerous cell. Therefore, the floxuridine kills the cancerous cells. For colorectal cancer and hepatic metastases, an average adult should be given an intra-arterial dosage of 0.1–0.6 mg/kg/day as a continuous infusion, continued until intolerable toxicity is reached (white blood cell count < 3,500/mm3 or platelet count < 100,000/mm3). [7] Lethal dosages for other species are below. [8] LD50 is the lethal dose at which half of organisms exposed to the drug die.

Species LD50 (mg/kg +/- SE)
Mouse 880 +/- 51
Rat 670 +/- 73
Rabbit 94 +/- 19.6
Dog 157 +/- 46

Pharmacodynamics

Floxuridine is a pyrimidine analog that acts as an inhibitor of the S-phase of cell division. This selectively kills rapidly dividing cells. Antimetabolites masquerade as pyrimidine-like molecules which prevents normal pyrimidines from being incorporated into DNA during the S phase of the cell cycle. Fluorouracil (the end-product of catabolism of floxuridine) blocks an enzyme which converts cytosine nucleosides into the deoxy derivative. In addition, DNA synthesis is further inhibited because fluorouracil blocks the incorporation of the thymidine nucleotide into the DNA strand.

Mechanism of action

Floxuridine is rapidly catabolized to 5-fluorouracil, which is the active form of the drug. The primary effect is interference with DNA synthesis and to a lesser extent, inhibition of RNA formation through the drug's incorporation into RNA, thus leading to the production of fraudulent RNA. Fluorouracil also inhibits uracil riboside phosphorylase, which prevents the utilization of preformed uracil in RNA synthesis. As well, the monophosphate of floxuridine, 5-fluoro-2'-deoxyuridine-5'-phosphate (FUDR-MP) inhibits the enzyme thymidylate synthetase. This leads to the inhibition of methylation of deoxyuridylic acid to thymidylic acid, thus interfering with DNA synthesis.

Route of elimination

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.

Side effects

Side effects include: [9]

Common (30% of patients)

Less common (10–29% of patients)

Contact your health provider immediately

Contact your health provider

Other

Use in research

Apart from its use in chemotherapy, floxuridine is also used in aging research employing a C. elegans model, namely to stop growth and to prevent reproduction. The latter is brought about by treatment of larvae close to maturity with low doses of floxuridine that, even though allowing normal maturation, causes reproducing individuals to lay eggs that are unable to hatch. [10] This limits the population to a single generation allowing quantification of aging processes and measurement of longevity. [11] It has, however, been indicated that floxuridin exposure by itself increases life expectancy potentially leading to flawed data in respective studies. [12]

History

Floxuridine first gained FDA approval in December 1970 under the brand name FUDR. The drug was initially marketed by Roche, which also did a lot of the initial work on 5-fluorouracil. The National Cancer Institute was an early developer of the drug. Roche sold its FUDR product line in 2001 to F H Faulding, which became Mayne Pharma.

Alternative names

Synonyms for floxuridine include: [13]

Related Research Articles

<span class="mw-page-title-main">Chemotherapy</span> Treatment of cancer using drugs that inhibit cell division or kill cells

Chemotherapy is a type of cancer treatment that uses one or more anti-cancer drugs as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent or it may aim to prolong life or to reduce symptoms. Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer, which is called medical oncology.

<span class="mw-page-title-main">Uracil</span> Chemical compound of RNA

Uracil is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced by thymine (T). Uracil is a demethylated form of thymine.

<span class="mw-page-title-main">Thymidine</span> Chemical compound

Thymidine, also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. In cell biology it is used to synchronize the cells in G1/early S phase. The prefix deoxy- is often left out since there are no precursors of thymine nucleotides involved in RNA synthesis.

Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer. As a cream it is used for actinic keratosis, basal cell carcinoma, and skin warts.

Transcatheter arterial chemoembolization (TACE) is a minimally invasive procedure performed in interventional radiology to restrict a tumor's blood supply. Small embolic particles coated with chemotherapeutic drugs are injected selectively through a catheter into an artery directly supplying the tumor. These particles both block the blood supply and induce cytotoxicity, attacking the tumor in several ways.

An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid; thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used as chemotherapy for cancer.

<span class="mw-page-title-main">Oxaliplatin</span> Pharmaceutical drug

Oxaliplatin, sold under the brand name Eloxatin among others, is a cancer medication used to treat colorectal cancer. It is given by injection into a vein.

<span class="mw-page-title-main">Clofarabine</span> Chemical compound

Clofarabine is a purine nucleoside antimetabolite marketed in the United States and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra. It is FDA-approved for treating relapsed or refractory acute lymphoblastic leukaemia (ALL) in children after at least two other types of treatment have failed. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out. Ongoing trials are assessing its efficacy for managing other cancers.

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer. It is made up of the following drugs:

<span class="mw-page-title-main">Raltitrexed</span> Chemical compound

Raltitrexed is an antimetabolite drug used in cancer chemotherapy. It is an inhibitor of thymidylate synthase, and is manufactured by AstraZeneca.

<span class="mw-page-title-main">Thymidylate synthase</span>

Thymidylate synthase (TS) is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleotides and increased levels of dUMP arise. Both cause DNA damage.

<span class="mw-page-title-main">Thymidine phosphorylase</span>

Thymidine phosphorylase is an enzyme that is encoded by the TYMP gene and catalyzes the reaction:

Hepatic arterial infusion (HAI) is a medical procedure that delivers chemotherapy directly to the liver. The procedure, mostly used in combination with systemic chemotherapy, plays a role in the treatment of liver metastases in patients with colorectal cancer (CRC). Although surgical resection remains the standard of care for these liver metastases, majority of patients have lesions that are unresectable.

Pyrimidine analogues are antimetabolites which mimic the structure of metabolic pyrimidines.

Thymidylate synthase inhibitors are chemical agents which inhibit the enzyme thymidylate synthase and have potential as an anticancer chemotherapy. This inhibition prevents the methylation of C5 of deoxyuridine monophosphate (dUMP) thereby inhibiting the synthesis of deoxythymidine monophosphate (dTMP). The downstream effect is promotion of cell death because cells would not be able to properly undergo DNA synthesis if they are lacking dTMP, a necessary precursor to dTTP. Five agents were in clinical trials in 2002: raltitrexed, pemetrexed, nolatrexed, ZD9331, and GS7904L.

<span class="mw-page-title-main">Trifluridine/tipiracil</span> Combination medication

Trifluridine/tipiracil, sold under the brand name Lonsurf, is a fixed-dose combination medication that is used as a third- or fourth-line treatment of metastatic colorectal cancer or gastric cancer, after chemotherapy and targeted therapeutics have failed. It is a combination of two active pharmaceutical ingredients: trifluridine, a nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor. Tipiracil prevents rapid metabolism of trifluridine, increasing the bioavailability of trifluridine.

Tegafur/gimeracil/oteracil, sold under the brand names Teysuno and TS-1, is a fixed-dose combination medication used for the treatment of advanced gastric cancer when used in combination with cisplatin, and also for the treatment of head and neck cancer, colorectal cancer, non–small-cell lung, breast, pancreatic, and biliary tract cancers.

FOLFOXIRI is a chemotherapy regimen for The treatment of advanced colorectal cancer. The role of FOLFOXIRI in colorectal cancer has been reviewed.

<span class="mw-page-title-main">Doxifluridine</span> Nucleoside analog prodrug

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. 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.

<span class="mw-page-title-main">Fluorodeoxyuridylate</span> Chemical compound

Fluorodeoxyuridylate, also known as FdUMP, 5-fluoro-2'-deoxyuridylate, and 5-fluoro-2'-deoxyuridine 5'-monophosphate, is a molecule formed in vivo from 5-fluorouracil and 5-fluorodeoxyuridine.

References

  1. ↑ "Floxuridine". PubChem. Retrieved 18 April 2017.
  2. ↑ Allen-Mersh TG, Earlam S, Fordy C, Abrams K, Houghton J (November 1994). "Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases". Lancet. 344 (8932): 1255–60. doi:10.1016/S0140-6736(94)90750-1. PMID   7526096. S2CID   35318063.
  3. ↑ "Floxuridine". Chemocare. Chemocare.com. Archived from the original on 24 April 2017. Retrieved 17 April 2017.
  4. ↑ Khaw PT, Sherwood MB, MacKay SL, Rossi MJ, Schultz G (August 1992). "Five-minute treatments with fluorouracil, floxuridine, and mitomycin have long-term effects on human Tenon's capsule fibroblasts". Archives of Ophthalmology. 110 (8): 1150–4. doi:10.1001/archopht.1992.01080200130040. PMID   1386726.
  5. ↑ Rivero CW, Britos CN, Lozano ME, Sinisterra JV, Trelles JA (June 2012). "Green biosynthesis of floxuridine by immobilized microorganisms". FEMS Microbiology Letters. 331 (1): 31–6. doi: 10.1111/j.1574-6968.2012.02547.x . PMID   22428623.
  6. ↑ Canadian Institutes of Health Research. "Floxuridine". DrugBank. Retrieved 18 April 2017.
  7. ↑ "Floxuridine". Drugs.com.
  8. ↑ "Floxuridine". Bedford Laboratories.
  9. ↑ "Floxuridine". Chemocare. Chemocare.com. Archived from the original on 24 April 2017. Retrieved 17 April 2017.
  10. ↑ Hosono, Ryuji (1978-01-01). "Sterilization and growth inhibition of Caenorhabditis elegans by 5-fluorodeoxyuridine". Experimental Gerontology. 13 (5): 369–373. doi:10.1016/0531-5565(78)90047-5. ISSN   0531-5565. PMID   153845. S2CID   46489154.
  11. ↑ Gandhi, Schiva; Santelli, John; Mitchell, David H.; Wesley Stiles, J.; Rao Sanadi, D. (February 1980). "A simple method for maintaining large, aging populations of Caenorhabditis elegans". Mechanisms of Ageing and Development. 12 (2): 137–150. doi:10.1016/0047-6374(80)90090-1. PMID   6445025. S2CID   44987472.
  12. ↑ Aitlhadj, Layla; Stürzenbaum, Stephen R. (May 2010). "The use of FUdR can cause prolonged longevity in mutant nematodes". Mechanisms of Ageing and Development. 131 (5): 364–365. doi:10.1016/j.mad.2010.03.002. ISSN   1872-6216. PMID   20236608. S2CID   39908205.
  13. ↑ Canadian Institutes of Health Research. "Floxuridine". DrugBank. Retrieved 18 April 2017.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.