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Inhibition by 5-fluorouracil of ERCC1 and gamma-glutamylcysteine synthetase messenger RNA expression in a cisplatin-resistant HST-1 human squamous carcinoma cell line.
Oncol Res. 1997; 9(4):167-72.OR

Abstract

Pretreatment of 5-fluorouracil (5-FU), but not posttreatment, has been shown to augment the cytotoxicity of cisplatin (CDDP) or even circumvent CDDP resistance by inhibiting repair of platinum-DNA interstrand crosslinks as well as by reducing the cellular glutathione (GSH) contents in CDDP-resistant HST-1/CP0.2 human squamous carcinoma cells. Because exogenous thymidine, which compensates for 5-FU-mediated inhibition of de novo DNA synthesis via salvage pathway, did not affect this schedule-dependent synergism, the modulatory effect of 5-FU on CDDP resistance would be attributed to the 5-FU-induced RNA damage. We therefore examined the effect of 5-FU on the steady-state levels of messenger RNA (mRNA) of a human excision repair gene ERCC1 and gamma-glutamylcysteine synthetase (gamma-GCS) gene coding for a rate-limiting enzyme for GSH synthesis. The HST-1/ CP0.2 cells were found to have significantly more mRNA expression of these respective genes than do parental HST-1 cells. In these cells, 5-FU pretreatment progressively inhibited mRNA expression of both ERCC1 and gamma-GCS after removal of 5-FU, without affecting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA. A maximal mRNA suppression was observed at 48 h posttreatment. Such 5-FU-induced suppression of mRNA transcripts of these genes seems to be consistent with its inhibitory activity on DNA repair capacity and cellular GSH contents. In contrast, 5-FU did not reduce the level of glutathione-S-transferase-pi (GST-pi) or DNA topoisomerase 1 mRNA. Although not convinced, our data suggest that 5-FU, when incorporated into RNA, may inhibit both GSH synthesis and repair of platinum-DNA adducts by downregulating the ERCC1 and gamma-GCS genes, thereby enhancing antitumor activity of CDDP and reversing resistance to CDDP in HST-1/CP0.2 cells.

Authors+Show Affiliations

First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9268987

Citation

Fujishima, H, et al. "Inhibition By 5-fluorouracil of ERCC1 and Gamma-glutamylcysteine Synthetase Messenger RNA Expression in a Cisplatin-resistant HST-1 Human Squamous Carcinoma Cell Line." Oncology Research, vol. 9, no. 4, 1997, pp. 167-72.
Fujishima H, Nakano S, Masumoto N, et al. Inhibition by 5-fluorouracil of ERCC1 and gamma-glutamylcysteine synthetase messenger RNA expression in a cisplatin-resistant HST-1 human squamous carcinoma cell line. Oncol Res. 1997;9(4):167-72.
Fujishima, H., Nakano, S., Masumoto, N., Esaki, T., Tatsumoto, T., Kondo, T., & Niho, Y. (1997). Inhibition by 5-fluorouracil of ERCC1 and gamma-glutamylcysteine synthetase messenger RNA expression in a cisplatin-resistant HST-1 human squamous carcinoma cell line. Oncology Research, 9(4), 167-72.
Fujishima H, et al. Inhibition By 5-fluorouracil of ERCC1 and Gamma-glutamylcysteine Synthetase Messenger RNA Expression in a Cisplatin-resistant HST-1 Human Squamous Carcinoma Cell Line. Oncol Res. 1997;9(4):167-72. PubMed PMID: 9268987.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition by 5-fluorouracil of ERCC1 and gamma-glutamylcysteine synthetase messenger RNA expression in a cisplatin-resistant HST-1 human squamous carcinoma cell line. AU - Fujishima,H, AU - Nakano,S, AU - Masumoto,N, AU - Esaki,T, AU - Tatsumoto,T, AU - Kondo,T, AU - Niho,Y, PY - 1997/1/1/pubmed PY - 1997/1/1/medline PY - 1997/1/1/entrez SP - 167 EP - 72 JF - Oncology research JO - Oncol. Res. VL - 9 IS - 4 N2 - Pretreatment of 5-fluorouracil (5-FU), but not posttreatment, has been shown to augment the cytotoxicity of cisplatin (CDDP) or even circumvent CDDP resistance by inhibiting repair of platinum-DNA interstrand crosslinks as well as by reducing the cellular glutathione (GSH) contents in CDDP-resistant HST-1/CP0.2 human squamous carcinoma cells. Because exogenous thymidine, which compensates for 5-FU-mediated inhibition of de novo DNA synthesis via salvage pathway, did not affect this schedule-dependent synergism, the modulatory effect of 5-FU on CDDP resistance would be attributed to the 5-FU-induced RNA damage. We therefore examined the effect of 5-FU on the steady-state levels of messenger RNA (mRNA) of a human excision repair gene ERCC1 and gamma-glutamylcysteine synthetase (gamma-GCS) gene coding for a rate-limiting enzyme for GSH synthesis. The HST-1/ CP0.2 cells were found to have significantly more mRNA expression of these respective genes than do parental HST-1 cells. In these cells, 5-FU pretreatment progressively inhibited mRNA expression of both ERCC1 and gamma-GCS after removal of 5-FU, without affecting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA. A maximal mRNA suppression was observed at 48 h posttreatment. Such 5-FU-induced suppression of mRNA transcripts of these genes seems to be consistent with its inhibitory activity on DNA repair capacity and cellular GSH contents. In contrast, 5-FU did not reduce the level of glutathione-S-transferase-pi (GST-pi) or DNA topoisomerase 1 mRNA. Although not convinced, our data suggest that 5-FU, when incorporated into RNA, may inhibit both GSH synthesis and repair of platinum-DNA adducts by downregulating the ERCC1 and gamma-GCS genes, thereby enhancing antitumor activity of CDDP and reversing resistance to CDDP in HST-1/CP0.2 cells. SN - 0965-0407 UR - https://www.unboundmedicine.com/medline/citation/9268987/Inhibition_by_5_fluorouracil_of_ERCC1_and_gamma_glutamylcysteine_synthetase_messenger_RNA_expression_in_a_cisplatin_resistant_HST_1_human_squamous_carcinoma_cell_line_ L2 - http://www.diseaseinfosearch.org/result/1077 DB - PRIME DP - Unbound Medicine ER -