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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
1Biosynthesis
2Pharmacology[6]
2.1Pharmacodynamics
2.2Mechanism of action
2.3Route of Elimination
3Side effects
3.1Common (30% of patients)
3.2Less common (10–29% of patients)
3.3Contact your health provider immediately
3.4Contact your health provider
3.5Other
4History
5Alternative names
6References
Biosynthesis
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]
Biosynthesis of Floxuridine
Pharmacology[6]
Floxuridine primarily works by stopping the growth of newly born cells. 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/mm^3 or platelet count <100,000/mm^3).[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 fluoruracil 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)
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)
Poor appetite
Nausea and vomiting
Hair loss
Elevated liver enzymes (temporary increase in alkaline phosphatase, lactate dehydrogenase, transaminase, and bilirubin). This is seen more with the intra-arterial infusion directly into the liver.
Hand-foot syndrome (Palmar-plantar erythrodysesthesia or PPE) -skin rash, swelling, redness, pain and/or peeling of the skin on the palms of hands and soles of feet
Stomach ulcers (This is seen more with the intra-arterial infusion).
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.
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.
^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". The Lancet. 344 (8932): 1255–1260. doi:10.1016/S0140-6736(94)90750-1.
^"Floxuridine". Chemocare. Chemocare.com. Retrieved 17 April 2017.
^Khaw, Peng T.; Sherwood, Mark B.; Mackay, Sally L. D. (August 1992). "Five-Minute Treatments With Fluorouracil, Floxuridine, and Mitomycin Have Long-term Effects on Human Tenon's Capsule Fibroblasts". JAMA Ophthalmology. 110 (8): 1150. doi:10.1001/archopht.1992.01080200130040. Retrieved 7 May 2017.
Among the various enzymes, reductases that catalyze one-electron reduction are involved in the selective activation of functional compounds or materials in hypoxia, which is one of the well-known pathophysiological characteristics of solid tumors. Enzymatic one-electron reduction has been recognized
Click and Release: A High-Content Bioorthogonal Prodrug with Multiple Outputs.
Ji X, Aghoghovbia RE, De La Cruz LKC, Pan Z, Yang X, Yu B, Wang B.
Organic letters. 2019 May;21(10)3649-3652.
A high-content bioorthogonal prodrug with multiple outputs using the "click, cyclize, and release" concept is described. The proof of concept is established by the co-delivery of a gasotransmitter carbon monoxide, an anticancer drug floxuridine, and an in situ generated fluorescent reporter molecule
Amide- and ester-linked kinase inhibitor-cytotoxin conjugates were rationally designed and synthesised as prototype hypoxia-activated anticancer mutual prodrugs. Chemical reduction of an aryl nitro trigger moiety was shown to initiate a spontaneous cyclisation/fragmentation reaction that simultaneou
50-91-9 5-fluorodeoxyuridine testing. Laboratory testing for CAS number 50-91-9. Floxuridine;Floxuridin;Fudr;Nsc 27640;2'-Deoxy-5-fluorouridine;5-Fluoro-2'-deoxyuridine;5-Fluorodeoxyuridine;5-Fluorouracil deoxyriboside;5-Fluorouracil ...
