Plasma, Intestine and Tumor Levels of 5-Fluorouracil in Mice Bearing L1210 Ascites Tumor Following Oral Administration of 5-Fluorouracil, UFT (Mixed Compound of Tegafur and Uracil), Carmofur and 5'-Deoxy-5-fluorouridine.

Ooi, Kazuya; Ohkubo, Toshiki; Higashigawa, Masamune; Kawasaki, Hajime; Kakito, Hideshi; Kagawa, Yoshiyuki; Kojima, Michio; Sakurai, Minoru

doi:10.1248/bpb.24.1329

Cited by 9 publications

(11 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a single study examining 5-fluorouracil alone, four repeated injections of 150 mg/kg 5-fluorouracil failed to alter maze performance in young female rats (Lee et al 2006), a result in contrast to the present findings. The doses of 75 mg/kg (present study) and 150 mg/kg (Lee et al 2006) 5-fluorouracil in mice and rats, respectively, fall slightly below and slightly above the predicted 100-mg/kg-scaled mouse dose as determined from the typical clinical dose used to treat breast cancer in humans (500 mg/m 2 ) (Gusella et al 2006;Jin et al 2005;Kralovanszky et al 1999;Ooi et al 2001;Peters et al 1993). The findings in the present study underscore the importance of examining a range of relevant preclinical and clinical doses in more than one type of assay to capture the relationship of chemotherapeutic agents to changes in different types of learning and memory behaviors.…”

Section: Discussionmentioning

confidence: 40%

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

2008

View full text Add to dashboard Cite

Rationale-The concern that adjuvant cancer chemotherapy agents cause cognitive impairment in a significant number of patients has been expressed by patients and healthcare providers, but clinical studies have yielded conflicting results to date.Objective-We directly tested two commonly used chemotherapeutic agents in a mouse model of learning and memory.Materials and methods-In the present study, mice were conditioned to respond for a liquid reinforcer (Ensure solution) in the presence of an audible tone on day 1 as a measure of acquisition and were then required to perform the same response on day 2 as a measure of retrieval and retention. Methotrexate and 5-fluorouracil were administered prior to the day 1 session.Results-Methotrexate (1.0-32 mg/kg) alone failed to alter mean latency acquisition, retrieval, or reinforced response rates. Similar to scopolamine, a known amnesic in this assay, 5-fluorouracil (3-75 mg/kg) failed to alter response rates or acquisition latency on day 1 but significantly altered latency to retrieve a previously learned response on day 2. In combination, 3.2 mg/kg methotrexate plus 75 mg/kg 5-fluorouracil significantly increased day 1 and day 2 acquisition and retrieval latencies without altering responserates or motivation to respond as measured by progressive ratio responding. Conclusion-Takentogether, these data demonstrate that 5-fluorouracil causes increased latencies for retrieval of previously learned behavioral responses and that combination of chemotherapeutic agents may produce greater delays than either agent alone, including when neither agent alone does so.

show abstract

Section: Discussionmentioning

confidence: 40%

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

2008

View full text Add to dashboard Cite

show abstract

“…Carmofur has been used to treat colorectal cancer since 1980s 8 , and has shown clinical benefits on breast, gastric, and bladder cancers 9-11 . The target for Carmofur is believed to be thymidylate synthase 12,13 , but it has also been shown to inhibit human acid ceramidase (AC) 14 , through covalent modification of its catalytic cysteine 15 .…”

Section: Figmentioning

confidence: 99%

Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug Carmofur

Jin

Zhao

Sun

et al. 2020

Preprint

View full text Add to dashboard Cite

25COVID-19 virus is the cause of a debilitating and life-threatening infectious 26 pulmonary disease that is now responsible for a global pandemic. Currently, there are 27 no specific drugs or vaccines to contain this virus. The main protease (M pro ) of COVID-28 19 virus is a key enzyme, which plays an essential role in viral replication and 29 transcription, making it an ideal drug target. An FDA-approved antineoplastic drug, 30 carmofur, has been identified as an inhibitor that targets COVID-19 virus M pro . 31However, its inhibitory mechanism is unknown. Here, we report the 1.6-Å crystal 32 structure of COVID-19 virus M pro in complex with carmofur. The crystal structure 33 shows that carmofur contains an electrophilic carbonyl reactive group, which 34 covalently binds to C145, a member of the catalytic dyad. As a result, its fatty acid tail 35 occupies the hydrophobic S2 subsite of M pro whilst its 5-fluorouracil head is cleaved as 36 product of the new covalent bond that has formed. Carmofur is active in a cell based 37 antiviral assay with an EC50 of 24.87 μM. It is therefore a promising lead compound 38 for the development of new antivirals to target COVID-19. : bioRxiv preprint 41 Starting in December 2019, a highly infectious viral disease has now spread and 42 reached over 200 countries leading to a global public health emergency and pandemic. 43The etiological agent of the disease is a coronavirus (identified as . 44According to the WHO COVID-2019 Situation Report-77, there were 1,210,956 45 confirmed cases and 67,594 deaths, with a mortality rate at 5.58%. The number of 46 confirmed cases worldwide continues to grow at a rapid rate and is far from peaking. 47However, there are no specific drugs or vaccines available to control symptoms or the 48 spread of this disease. 49The COVID-19 virus has a ~30,000 nt RNA genome encoded with two translation 50 products, polyproteins 1a and 1ab (pp1a and pp1ab) which are crucial for replication 51 and transcription 1,2 . These polyproteins become matured non-structural and structural 52 proteins through auto-cleavage by the main protease (M pro ) and by a papain-like 53 protease 3 . Because of this, M pro is an excellent target for anti-coronavirus (CoV) drug 54 development 4-6 . In order to rapidly discover new drug leads that target COVID-19 virus 55 M pro , our group screened over 10,000 compounds from a library that consisted of 56 approved drugs, drug candidates in clinical trials, and other pharmacologically active 57 compounds. Amongst these we identified carmofur as compound that can inhibit M pro 58 with an IC50 of 1.82 μM 7 . 59Carmofur is an FDA-approved antineoplastic drug, and a derivative of 5-60 fluorouracil (5-FU) a widely drug used against solid cancers. 5-FU is especially 61 efficient for controlling head, neck, and gastrointestinal tumors 8 . Carmofur (Figure 1A) 62 is a derivative of this compound and has been used in colon cancer therapy since 1981 9 . 63Clinical research has also shown that carmofur has a curative effect on breast, gastri...

show abstract

“…Early studies suggested that the hexylcarbamoyl structure (more lipophilic) eases the transport of carmofur through the cell membrane, providing a higher therapeutic ratio 4 . For more than 30 years, carmofur has been considered a masked compound of 5-FU, and believed to functions similarly to 5-FU 5, 6 . However, some researchers have questioned this mechanism as carmofur was also as effective in targeting 5-FU resistant cells compared to control 6 .…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of Inhibition of Acid Ceramidase by Carmofur

et al. 2018

View full text Add to dashboard Cite

Human acid ceramidase (AC) is a lysosomal cysteine amidase, which has received a great deal of interest in recent years as a potential target for the development of new therapeutics against melanoma and glioblastoma tumors. Despite the strong interest in obtaining structural information, only the structures of the apo-AC enzyme in its zymogen and activated conformations are available. In this work, the crystal structure of AC in complex with the covalent carmofur inhibitor is presented. Carmofur is an antineoplastic drug containing an electrophilic carbonyl reactive group that targets the catalytic cysteine. This novel structural data explains the basis of the AC inhibition, provides insights into the enzymatic properties of the protein, and is a great aid toward the structure-based drug design of potent inhibitors for AC, providing the detailed mechanism, which has eluded the scientific community for more than 30 years, of carmofur's mysterious 5fluorouracil-independent anti-tumor activity.

show abstract

Plasma, Intestine and Tumor Levels of 5-Fluorouracil in Mice Bearing L1210 Ascites Tumor Following Oral Administration of 5-Fluorouracil, UFT (Mixed Compound of Tegafur and Uracil), Carmofur and 5'-Deoxy-5-fluorouridine.

Cited by 9 publications

References 14 publications

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug Carmofur

Molecular Mechanism of Inhibition of Acid Ceramidase by Carmofur

Contact Info

Product

Resources

About