Carmofur (INN) orHCFU (1-hexylcarbamoyl-5-fluorouracil) is apyrimidine analogue used as anantineoplastic agent. It is a derivative offluorouracil, being a lipophilic-masked analog of 5-FU that can be administered orally.[1]
Carmofur prodrug is ingested and taken up in the intestine, overcoming the problem of 5-FU degradation bydihydropyrimidine dehydrogenase. Once inside a cell, the carmofur prodrug is converted into 5-FU.
The mechanism of action of carmofur prodrug is traditionally thought to be the generation of5–FU.[2] However, carmofur is a highly potentacid ceramidase (AC) inhibitor.[2]Ceramide influences cancer cell survival, growth and death.[2] Inhibition of AC activity sensitizes tumor cells to the effects of antineoplastic agents and radiation.[2] Carmofur, much more effective thantemozolomide, has been reported as the small-molecule drug capable of killing adult and pediatricglioblastomas.[3][4]
Product marketing for carmofur started in 1981. Carmofur has also been used as adjuvant chemotherapy for curatively resectedcolorectal cancer patients in China, Japan, and Finland for many years.[5] Trials andmeta-analyses have confirmed that the drug is effective on patients with this cancer type, extending their survival.[6]
Carmofur has been shown to inhibit theSARS-CoV-2 main protease, and is therefore a promising lead compound to develop new antiviral treatment forCOVID-19.[7]
As fluorouracil, carmofur has been known to induceleukoencephalopathy, characterized by progressive damage to white matter in the brain with stroke-like symptoms.[8][9][10]
A clinical trial for small hepatocellular carcinoma was stopped prematurely because 56% of the treated patients had unacceptable side effects. Moreover, the treatment had no survival advantage for stage 1 and 2 cancer patients.[11] This may be a reason why carmofur was never pursued for FDA-approval in the US.[1]
Ozaki et al. have reported a synthesis by treating 5-FU with phosgene and hexylamine.[12] Xiong et al. reported an alternative approach for the synthesis of carmofur . Chemical preparations and structures can be found here.[1]
^Sakamoto J, Oba K, Matsui T, Kobayashi M (October 2006). "Efficacy of oral anticancer agents for colorectal cancer".Diseases of the Colon and Rectum.49 (10 Suppl):S82 –S91.doi:10.1007/s10350-006-0601-7.PMID17106820.S2CID30655861.
^Yamada T, Okamura S, Okazaki T, Ushiroyama T, Yanagawa Y, Ueki M, et al. (June 1989). "Leukoencephalopathy following treatment with carmofur: a case report and review of the Japanese literature".Asia-Oceania Journal of Obstetrics and Gynaecology.15 (2):161–168.doi:10.1111/j.1447-0756.1989.tb00171.x.PMID2667512.
^Mizutani T (February 2008). "[Leukoencephalopathy caused by antineoplastic drugs]".Brain and Nerve = Shinkei Kenkyu No Shinpo (in Japanese).60 (2):137–141.PMID18306661.
^Baehring JM, Fulbright RK (May 2008). "Delayed leukoencephalopathy with stroke-like presentation in chemotherapy recipients".Journal of Neurology, Neurosurgery, and Psychiatry.79 (5):535–539.doi:10.1136/jnnp.2007.123737.PMID17682013.S2CID38293604.
^Ozaki S, Nagase T, Ahmad S, Tamai H, Hoshi A, Iigo M (1987). "Synthesis and antitumor activity of 1- or 3-(alpha-hetero substituted)alkyl-5-fluorouracil derivatives".Nucleic Acids Symposium Series.18 (18):1–4.PMID3697106.
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