Establishment and characterization of 5-fluorouracil-resistant gastric cancer cells.
Two 5-fluorouracil (5-FU)-resistant cell lines from a Korean gastric cancer cell line were established by incubation of the cells with increasing concentration of 5-FU, and the resultant cell lines showed an over 800-fold increased resistance to 5-FU. To identify the mechanism of 5-FU resistance, the expressions of genes involved in 5-FU metabolism were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Expressions of orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and uridine phosphorylase (UP) were significantly downregulated in these cell lines, resulting in low incorporation of 5-FU into nucleic acids. In contrast, an increased expression of thymidine kinase (TK) was observed in 5-FU-resistant cells. These results strongly indicate that blocking of 5-FU incorporation into nucleic acids and TK overexpression may play a major role in 5-FU resistance in these cells. Interestingly, these cell lines showed cross-resistance to paclitaxel, cisplatin, and doxorubicin, suggesting that other factors such as HSP27 and Mn-SOD could be also involved in the mechanism of multidrug resistance in these cell lines.
Chung
Y M
YM
Laboratory of Experimental Therapeutics, Korea Cancer Center Hospital, 215-4 Gongneung-Dong, Nowon-Ku, 139-706, Seoul, South Korea.
Park
S
S
Park
J K
JK
Kim
Y
Y
Kang
Y
Y
Yoo
Y D
YD
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009962:Orotate Phosphoribosyltransferase / Q000235:genetics; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics; D013939:Thymidine Phosphorylase / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014543:Uridine Phosphorylase / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D012313:RNA; D004247:DNA; D013482:Superoxide Dismutase; D009962:Orotate Phosphoribosyltransferase; D014543:Uridine Phosphorylase; D013939:Thymidine Phosphorylase; D013937:Thymidine Kinase; D005472:Fluorouracil