Carmofur (
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
) or HCFU (1-hexylcarbamoyl-5-fluorouracil) is a
pyrimidine analogue used as an
antineoplastic agent. It is a derivative of
fluorouracil
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, pan ...
, being a lypophilic-masked analog of 5-FU that can be administered orally.
Biology
Carmofur prodrug is ingested and taken up in the intestine, overcoming the problem of 5-FU degradation by
dihydropyrimidine dehydrogenase
In enzymology, a dihydropyrimidine dehydrogenase (NADP+) () is an enzyme that catalyzes the chemical reaction
:5,6-dihydrouracil + NADP+ \rightleftharpoons uracil + NADPH + H+
Thus, the two substrates of this enzyme are 5,6-dihydrouracil an ...
. Once inside a cell, carmofur prodrug is converted into 5-FU.
Mechanism of action
The mechanism of action of carmofur prodrug is traditionally thought to be the generation of
5–FU.
[ However, carmofur is a highly potent acid ceramidase (AC) inhibitor.][ ]Ceramide
Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetyl sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make ...
influences cancer cell survival, growth and death.[ Inhibition of AC activity sensitizes tumor cells to the effects of antineoplastic agents and radiation.]temozolomide
Temozolomide (TMZ), sold under the brand name Temodar among others, is a medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. Text was copied from this source which is © European Medicines Agency. Reproduction ...
, has been reported as the small-molecule drug capable of killing adult and pediatric glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...
s.
Medicinal uses
Product marketing for carmofur started in 1981. Carmofur has also been used as adjuvant chemotherapy for curatively resected colorectal cancer patients in China, Japan, and Finland for many years.meta-analyses
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...
have confirmed that the drug is effective on patients with this cancer type, extending their survival.
Carmofur has been shown to inhibit the SARS-CoV-2 main protease, and is therefore a promising lead compound to develop new antiviral treatment for COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quickly ...
.
Adverse effects
As fluorouracil, carmofur has been known to induce leukoencephalopathy Leukoencephalopathy (leukodystrophy-like diseases) is a term that describes all of the brain white matter diseases, whether their molecular cause is known or unknown. It can refer specifically to any of these diseases:
*Progressive multifocal leuko ...
, characterized by progressive damage to white matter in the brain with stroke-like symptoms.
Chemical synthesis
Ozaki et al. has reported carmofur synthesized by treating 5-FU with phosgene and hexylamine.
References
{{Chemotherapeutic agents
Pyrimidinediones
Organofluorides
Pyrimidine antagonists
Fluoropyrimidines
SARS-CoV-2 main protease inhibitors