Mechanisms of collateral sensitivity to fluorouracil of a cis-diamminedichloroplatinum(II)-resistant human non-small lung cancer cell line
| Autor: | Nagahiro Saijo, Yuichiro Ohe, Tohru Ohmori, Toshihiko Morikage, Yasuhiro Fujiwara, Yoshikazu Sugimoto, Kazuto Nishio |
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| Rok vydání: | 1992 |
| Předmět: |
inorganic chemicals
Cancer Research Lung Neoplasms Drug Resistance Biology Adenocarcinoma In Vitro Techniques Bleomycin Thymidylate synthase chemistry.chemical_compound Carcinoma Non-Small-Cell Lung medicine Tumor Cells Cultured Humans Thymine Nucleotides RNA Neoplasm Cytotoxicity neoplasms Uridine Etoposide Cisplatin Biological Transport female genital diseases and pregnancy complications Oncology Biochemistry Mechanism of action chemistry Cell culture Fluorouracil Cancer research biology.protein medicine.symptom medicine.drug DNA Damage Research Article |
| Zdroj: | British Journal of Cancer |
| ISSN: | 0007-0920 |
| Popis: | A cisplatin(CDDP)-resistant subline of a human lung cancer cell line, PC-7/CDDP, was 4.7-fold more resistant to CDDP than the parent line in a colony-forming assay. The sensitivity of this cell line to anthracyclines, vinca-alkaloid, etoposide, mitomycin C, and bleomycin was similar to that of the parental line, PC-7. However, PC-7/CDDP exhibited 4-fold higher sensitivity to fluorouracil (FUra). Possible mechanisms associated with the collateral sensitivity to FUra were studied in PC-7/CDDP cells. The sensitivity of both cell lines to FUra did not correlate with the effect of FUra on RNA. On the other hand, FUra induced a greater reduction in dTTP pools and more single strand breaks in PC-7/CDDP than in PC-7 cells. These results suggest that the pathway for de novo deoxyribonucleotide synthesis may be a target for FUra in PC-7/CDDP cells. However, inhibition of thymidylate synthase after FUra treatment did not correlate with the DNA-directed activity of FUra. Based on the above findings, the decreased salvage synthesis of dTTP was considered a possible mechanism of the greater reduction of dTTP pools in PC-7/CDDP cells. However, the activity of dThd kinase was the same in both cell lines. In the presence of physiological concentrations of exogenous dThd in the serum, uptake of dThd was less in PC-7/CDDP cells than that in PC-7 cells. Our data suggest that FUra-induced cytotoxicity in PC-7/CDDP cells is associated with the inhibition of dTTP synthesis and that the decreased uptake of dThd is a possible mechanism of the collateral sensitivity to FUra in PC-7/CDDP cells. |
| Databáze: | OpenAIRE |
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