Leukoencephalopathy Following Treatment with Carmofur: A Case Report and Review of the Japanese Literature

Yamada, Takashi; Okamura, Shinsuke; Okazaki, Tadashi; Ushiroyama, Takahisa; Yanagawa, Yasuhiko; Ueki, Minoru; Sugimoto, Osamu; Yamazaki, Hidetomo; Sugino, Masakazu; Masui, Yoshikazu

doi:10.1111/j.1447-0756.1989.tb00171.x

Cited by 9 publications

(9 citation statements)

References 3 publications

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“…Carmofur 24 has been used to treat colorectal cancer in China, Japan, and Finland for many years . However, the agent has been shown to induce delayed leukoencephalopathy, characterized by progressive damage to white matter in the brain with stroke-like symptoms. − There are currently no open clinical trials for this agent. A trial treating patients with stage II hepatocellular carcinoma was suspended prematurely, because 56% of the treated patients had unacceptable side effects and offered no survival advantage for certain cancers in stage 1 and 2 of the disease .…”

Section: Pyrimidine Analogsmentioning

confidence: 99%

Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs

et al. 2016

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Nucleoside, nucleotide, and base analogs have been in the clinic for decades to treat both viral pathogens and neoplasms. More than 20% of patients on anticancer chemotherapy have been treated with one or more of these analogs. This review focuses on the chemical synthesis and biology of anticancer nucleoside, nucleotide, and base analogs that are FDA-approved and in clinical development since 2000. We highlight the cellular biology and clinical biology of analogs, drug resistance mechanisms, and compound specificity towards different cancer types. Furthermore, we explore analog syntheses as well as improved and scale-up syntheses. We conclude with a discussion on what might lie ahead for medicinal chemists, biologists, and physicians as they try to improve analog efficacy through prodrug strategies and drug combinations.

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Section: Pyrimidine Analogsmentioning

confidence: 99%

Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs

et al. 2016

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“…However, treatment with carmofur did not extend the lifespan of twitcher mice ( 63 ); rather, it was only effective in twitcher mice that were also heterozygous for acid ceramidase deficiency ( 5 ). Unfortunately, human cancer patients treated with carmofur can have drug related side effects that include leukoencephalopathy, liver dysfunction, neuropathy, skin rash, and diarrhea ( 64 – 67 ). The potential side effect of leukoencephalopathy is worrisome since the pathological changes ongoing in Krabbe disease may make the patient more susceptible to this adverse effect.…”

Section: Substrate Reduction Therapy Targeting Acid Ceramidasementioning

confidence: 99%

Substrate Reduction Therapy for Krabbe Disease: Exploring the Repurposing of the Antibiotic D-Cycloserine

Levine

Tsau

2022

Front. Pediatr.

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Krabbe disease is a lysosomal storage disease that is caused by a deficiency in galactosylceramidase. Infantile onset disease is the most common presentation, which includes progressive neurological deterioration with corresponding demyelination, development of globoid cells, astrocyte gliosis, etc. Hemopoietic stem cell transplantation (HSCT) is a disease modifying therapy, but this intervention is insufficient with many patients still experiencing developmental delays and progressive deterioration. Preclinical studies have used animal models, e.g., twitcher mice, to test different experimental therapies resulting in developments that have led to progressive improvements in the therapeutic impact. Some recent advances have been in the areas of gene therapy and substrate reduction therapy (SRT), as well as using these in combination with HSCT. Unfortunately, new experimental approaches have encountered obstacles which have impeded the translation of novel therapies to human patients. In an effort to identify a safe adjunct therapy, D-cycloserine was tested in preliminary studies in twitcher mice. When administered as a standalone therapy, D-cycloserine was shown to lengthen the lifespan of twitcher mice in a small but significant manner. D-Cycloserine is an FDA approved antibiotic used for drug resistant tuberculosis. It also acts as a partial agonist of the NMDA receptor, which has led to numerous human studies for a range of neuropsychiatric and neurological conditions. In addition, D-cycloserine may inhibit serine palmitoyltransferase (SPT), which catalyzes the rate-limiting step in sphingolipid production. The enantiomer, L-cycloserine, is a much more potent inhibitor of SPT than D-cycloserine. Previously, L-cycloserine was found to act as an effective SRT agent in twitcher mice as both a standalone therapy and as part of combination therapies. L-Cycloserine is not approved for human use, and its potent inhibitory properties may limit its ability to maintain a level of partial inactivation of SPT that is also safe. In theory, D-cycloserine would encompass a much broader dosage range to achieve a safe degree of partial inhibition of SPT, which increases the likelihood it could advance to human studies in patients with Krabbe disease. Furthermore, additional properties of D-cycloserine raise the possibility of other therapeutic mechanisms that could be exploited for the treatment of this disease.

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“…The cause of pollakiuria was also identified as associated with stimulation on micturition reflex center in brain by CPEFU (Koyama, 1981). Later studies reported leukoencephalopathy with stroke like symptoms which gradually damaged the white matter of the brain (Baehring & Fulbright, 2008; Fujikawa et al, 2001; Kuzuhara et al, 1987; Matsumoto et al, 1995; Yamada et al, 1989). Another case study presented carmofur induced organic mental disorder during the prognostic phase after the inception of leukoencephalopathy (Suzuki et al, 1990).…”

Section: Side Effect(s) With Carmofur Therapymentioning

confidence: 99%

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

Islam

Mirza

2022

Drug Development Research

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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.

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Leukoencephalopathy Following Treatment with Carmofur: A Case Report and Review of the Japanese Literature

Cited by 9 publications

References 3 publications

Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs

Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs

Substrate Reduction Therapy for Krabbe Disease: Exploring the Repurposing of the Antibiotic D-Cycloserine

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

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