Document Detail


Apoptosis and thymidylate synthase inductions by 5-fluorouracil in gastric cancer cells with or without p53 mutation.
MedLine Citation:
PMID:  11445854     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We studied apoptosis and thymidylate synthase (TS) inductions by 5-fluorouracil (5-FU) in gastric cancer cells with wild-type p53 (MKN-45 and MKN-74) and with mutated p53 (MKN-28 and KATO-III). Apoptotic inductions in MKN-45 and MKN-74 were stronger than those in MKN-28 and KATO-III, suggesting that wild-type p53 may contribute to the induction of apoptosis. After continuous exposure to 0.1 microg/ml of 5-FU for 96 h, no TS induction was obtained in KATO-III, while approximately twice the amount of TS was observed compared to non-treatment cells in MKN-45, MKN-74, and MKN-28. The results of immunohistochemical staining for TS and p53 showed no relation between these two protein expressions in endoscopic biopsy specimens of 25 patients with advanced gastric cancer. These results indicated that p53 status may not play a pivotal role in regulating TS expression. We found no significantly different effects of 5-FU between intermittent (repeat of 24-h continuous infusion and 24-h drug-free) and continuous treatments in either MKN-28 or stem cells (CD34+ hematopoietic progenitor cells) when the same area under the time-concentration curve of 5-FU was administered. The TS induction in MKN-28 cells by intermittent treatment was significantly higher than that by continuous treatment; however, most TSs in both types of 5-FU treatment cells were of the inactive form, i.e., TS bound to FdUMP, a 5-FU metabolite. Therefore, neither intermittent nor continuous treatment appears to induce 5-FU resistance related to the level of increment free TS. In conclusion, our observations suggested that p53 mutation may be associated with apoptotic induction by 5-FU; however, p53 status may not strongly affect TS induction by 5-FU. Intermittent treatment can be replaced with continuous treatment without causing 5-FU resistance.
Authors:
K Yukimoto; B Nakata; K Muguruma; M Yashiro; M Ohira; T Ishikawa; M Hino; K Hirakawa
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  International journal of oncology     Volume:  19     ISSN:  1019-6439     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2001 Aug 
Date Detail:
Created Date:  2001-07-10     Completed Date:  2001-10-04     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  373-8     Citation Subset:  IM    
Affiliation:
Department of Surgical Oncology (First Department of Surgery), Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
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MeSH Terms
Descriptor/Qualifier:
Antimetabolites, Antineoplastic / pharmacology*
Apoptosis / drug effects*
Cell Survival / drug effects
DNA Mutational Analysis
DNA, Neoplasm / chemistry,  genetics
Fluorouracil / pharmacology*
Humans
Immunohistochemistry
In Situ Nick-End Labeling
Mutation
Polymorphism, Single-Stranded Conformational
Stomach Neoplasms / drug therapy,  genetics,  pathology*
Thymidylate Synthase / drug effects*,  metabolism
Tumor Cells, Cultured / drug effects,  metabolism
Tumor Suppressor Protein p53 / genetics*,  metabolism
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/DNA, Neoplasm; 0/Tumor Suppressor Protein p53; 51-21-8/Fluorouracil; EC 2.1.1.45/Thymidylate Synthase

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