Versatile use of Carmofur: A comprehensive review of its chemistry and pharmacology

Abstract

Carmofur, 1-hexylcarbamoyl-5-fluorouracil (HCFU) is an antineoplastic drug, which has been in clinics in Japan since 1981 for the treatment of colorectal cancer.Subsequently, it was also introduced in China, Korea, and Finland. Besides colorectal cancer, it has also shown antitumor activity in other cancers such as breast, head and neck, pancreatic, gastrointestinal, and solid brain tumors. A prodrug of 5-fluorouracil(5-FU), carmofur has shown better gastrointestinal stability and superior antiproliferative activity compared to its active counterpart 5-FU. Recently, carmofur has gained attention as an acid ceramidase inhibitor and as a potential lead compound against several noncancerous diseases such as coronavirus disease 2019, Krabbe disease, acute lung injury, Parkinson's disease, dementia, childhood ependymoma etc. Carmofur has also been reported to have antifungal, and antimicrobial properties. Nevertheless, no comprehensive review is available on this drug. Herein, we summarized the chemistry, pharmacokinetics, and pharmacology of carmofur based on the literature published between January 1976 and March 2022 as identified from PubMed and Google Scholar search engines.

Activity‐Based Protein Profiling in Methicillin‐Resistant Staphylococcus aureus Reveals the Broad Reactivity of a Carmofur‐Derived Probe

“…In light of the clinical use of carmofur as a drug in colorectal cancer (as reviewed in ref. [13]) it must be considered that this drug might exhibit a similarly broad reactivity profile against human enzymes that could be potentially be related to both therapeutic and side effects. It is also plausible that carmofur reacts promiscuously with enzymes from humanassociated microbiota.…”

“…[10] Carmofur, or 1-hexylcarbamoyl-5fluorouracil, is a registered anti-neoplastic drug for treatment for colorectal cancer in several countries [11,12] and a number of other potential therapeutic applications are under investigation as summarized in a recent review. [13] Carmofur is a prodrug of the antimetabolite 5-fluorouracil (5-FU) and its bioconversion pathways and known mechanism of action are illustrated in Scheme 1C. In human cells, 5-FU is converted to various bioactive metabolites that, in a complex mechanism, ultimately result in DNA damage and cell death.…”

“…One interesting candidate for this approach are carmofur‐derived probes (Scheme 1) that were generated to target human acid ceramidase (ACase) [9] after carmofur had been identified as a potent inhibitor of ACase [10] . Carmofur, or 1‐hexylcarbamoyl‐5‐fluorouracil, is a registered anti‐neoplastic drug for treatment for colorectal cancer in several countries [11,12] and a number of other potential therapeutic applications are under investigation as summarized in a recent review [13] . Carmofur is a prodrug of the antimetabolite 5‐fluorouracil (5‐FU) and its bioconversion pathways and known mechanism of action are illustrated in Scheme 1C.…”

Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex

“…Carmofur, a derivative of 5-fluorouracil, is a broad-spectrum antimetabolite that affects a wide range of pathways. Studies of carmofur activity in colorectal cancer cells ( 47 ), patients with colorectal carcinoma ( 48 ), glioblastoma cells ( 49 ), and breast cancer cells ( 50 ) demonstrate that carmofur is effective in suppressing ASAH1 expression.…”