Abstract | BACKGROUND & AIMS: METHODS: RESULTS: In vivo, 5-FU alone inhibited growth of only 3 of the 12 hCRCs tested and 3n-But alone had no effect; the 5-FU/3n-But combination inhibited growth of all 16 hCRCs tested. The hCRCs differed in their p53 and microsatellite instability status. 5-FU/3n-But decreased TK and TS mRNA expression by 20- and 40-fold, respectively, and TS activity by 75%, stopped cell proliferation without affecting cell differentiation, and significantly enhanced apoptosis. 3n-But potentiated the efficacy of Tomudex and methotrexate, 2 TS inhibitors, but not that of oxaliplatin. In vitro, 5-FU/3n-But inhibited [3H] thymidine but not bromodeoxyuridine incorporation and induced apoptosis in hCRC cell lines. Cells treated with 5-FU/3n-But did not accumulate in G1 nor in S phase of the cell cycle, while 5-FU and 3n-But arrested the cycle in S and in G1 phase, respectively. 3n-But prevented the cell rescue from 5-FU-induced cytotoxicity by uridine or thymidine. CONCLUSIONS:
3n-But and TS inhibitors acted synergistically against colorectal cancers, independently of the genetic alterations of the hCRCs. The mechanism of action of 5-FU/3n-But could be enhanced reduction of TS and prevention of thymidine salvage in DNA synthesis.
|
Authors | R A Bras-Gonçalves, M Pocard, J L Formento, F Poirson-Bichat, G De Pinieux, I Pandrea, F Arvelo, G Ronco, P Villa, A Coquelle, G Milano, T Lesuffleur, B Dutrillaux, M F Poupon |
Journal | Gastroenterology
(Gastroenterology)
Vol. 120
Issue 4
Pg. 874-88
(Mar 2001)
ISSN: 0016-5085 [Print] United States |
PMID | 11231942
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Antimetabolites, Antineoplastic
- Biomarkers
- Butyrates
- Organoplatinum Compounds
- Quinazolines
- RNA, Messenger
- Thiophenes
- Oxaliplatin
- esterbut-3
- DNA
- Oxidoreductases
- Dihydrouracil Dehydrogenase (NADP)
- Thymidylate Synthase
- Protein-Tyrosine Kinases
- raltitrexed
- Glucose
- Fluorouracil
- Methotrexate
|
Topics |
- Animals
- Antimetabolites, Antineoplastic
(administration & dosage, pharmacology)
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology)
- Apoptosis
(drug effects)
- Biomarkers
- Butyrates
(administration & dosage, pharmacology)
- Cell Differentiation
(drug effects)
- Cell Division
(drug effects)
- Colorectal Neoplasms
(metabolism, pathology)
- DNA
(biosynthesis)
- Dihydrouracil Dehydrogenase (NADP)
- Drug Synergism
- Female
- Fluorouracil
(administration & dosage, pharmacology)
- Glucose
(administration & dosage, analogs & derivatives, pharmacology)
- Humans
- Liver Neoplasms
(metabolism, pathology, secondary)
- Male
- Methotrexate
(administration & dosage)
- Mice
- Mice, Nude
- Neoplasm Transplantation
- Organoplatinum Compounds
(administration & dosage)
- Oxaliplatin
- Oxidoreductases
(metabolism)
- Protein-Tyrosine Kinases
(genetics)
- Quinazolines
(administration & dosage)
- RNA, Messenger
(metabolism)
- Thiophenes
(administration & dosage)
- Thymidylate Synthase
(genetics, metabolism)
- Transplantation, Heterologous
|
|
Join CureHunter, for free Research Interface BASIC access!
Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease.
Find out why thousands of doctors, pharma researchers and patient activists
around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!
|