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Floxuridine

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Floxuridine
Clinical data
AHFS/Drugs.comMonograph
MedlinePlusa682006
Routes of
administration		Intra-arterial
ATC code
Legal status
Legal status
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 InfoCard100.000.066 Edit this at Wikidata
Chemical and physical data
FormulaC9H11FN2O5
Molar mass246.194 g·mol−1
3D model (JSmol)
Melting point150.5 °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 checkY
  • Key:ODKNJVUHOIMIIZ-RRKCRQDMSA-N checkY
  (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.[2] 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.[3] Floxuridine can also be prescribed for the treatment of kidney and stomach cancers.[4] In vitro uses of floxuridine include 5-minute treatments of fluorouracil, floxuridine, and mitomycin to increase cell proliferation in Tenon's capsule fibroblasts.[5]

Biosynthesis

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.[6]

Pharmacology

Floxuridine primarily works by stopping the growth of newly born cells.[7] 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).[8] Lethal dosages for other species are below.[9] 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:[10]

Common (30% of patients)

  • Low blood counts. Your white and red blood cells and platelets may temporarily decrease. This can put you at increased risk for infection, anemia and/or bleeding.
  • Mouth sores
  • Diarrhea (may be severe)

Less common (10–29% of patients)

Contact your health provider immediately

  • Fever of 100.4 °F (38 °C) or higher, chills (possible signs of infection).

Contact your health provider

  • Diarrhea (2 episodes in a 24-hour period)
  • Nausea (interferes with ability to eat and unrelieved with prescribed medication)
  • Vomiting (vomiting more than 4–5 times in a 24-hour period)
  • Mouth sores (painful redness, swelling or ulcers)
  • Unusual bleeding or bruising
  • Black or tarry stools, or blood in your stools
  • Blood in the urine
  • Yellowing of the skin or eyes
  • Tingling or burning, redness, swelling of the palms of the hands or soles of feet

Other

  • Fertility for both men and women may be affected by floxuridine.

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.[11] This limits the population to a single generation allowing quantification of aging processes and measurement of longevity.[12] It has, however, been indicated that floxuridin exposure by itself increases life expectancy potentially leading to flawed data in respective studies.[13]

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:[14]

  • 5 Fluorodeoxyuridine
  • 5-Fluorodeoxyuridine
  • 5-FUdR
  • Floxuridine
  • Fluorodeoxyuridine
  • FUdR
  • 50-91-9
  • 2'-Deoxy-5-fluorouridine
  • 5-Fluoro-2'-deoxyuridine
  • 5-Fluorodeoxyuridine
  • FUDR
  • 5 Fluorodeoxyuridine
  • Fluorodeoxyuridine
  • Floxuridin
  • Fluoruridine deoxyribose
  • Deoxyfluorouridine
  • Floxiridina
  • Floxuridinum
  • 5-Fluorouracil deoxyriboside
  • 5-Fluoro-2-desoxyuridine
  • 5FdU
  • 5-Fluoro-2-deoxyuridine
  • beta-5-Fluoro-2'-deoxyuridine
  • FdUR
  • 5-fluoro-1-((2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1h,3h)-dione
  • FdUrd
  • 1-(2-Deoxy-beta-D-ribofuranosyl)-5-fluorouracil
  • Uridine, 2'-deoxy-5-fluoro-
  • 1beta-D-2'-Deoxyribofuranosyl-5-flurouracil
  • 1-beta-D-2'-Deoxyribofuranosyl-5-flurouracil
  • UNII-039LU44I5M
  • 5-Fluorouracil 2'-deoxyriboside
  • Floxuridinum [INN-Latin]
  • Floxiridina [INN-Spanish]
  • 5-FdUrd

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ "Floxuridine". PubChem. Retrieved 18 April 2017.
  3. ^ 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.
  4. ^ "Floxuridine". Chemocare. Chemocare.com. Archived from the original on 24 April 2017. Retrieved 17 April 2017.
  5. ^ 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.
  6. ^ 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.
  7. ^ Canadian Institutes of Health Research. "Floxuridine". DrugBank. Retrieved 18 April 2017.
  8. ^ "Floxuridine". Drugs.com.
  9. ^ "Floxuridine". Bedford Laboratories.
  10. ^ "Floxuridine". Chemocare. Chemocare.com. Archived from the original on 24 April 2017. Retrieved 17 April 2017.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ Canadian Institutes of Health Research. "Floxuridine". DrugBank. Retrieved 18 April 2017.
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