Collateral sensitivity of cisplatin-resistant human lung cancer cell lines to thymidylate synthase inhibitors

Y. Ohe, Yoshikazu Sugimoto, N. Saijo

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The sensitivity of three cisplatin-resistant human non-small cell lung cancer cell lines, PC-7/1.0, PC-9/0.5, and PC-14/1.5 cells, to 5-fluorouracil was compared with that of the parental cell lines. The 50% inhibitory concentrations (IC50) value of 5-fluorouracil for PC-7/1.0 cells was 4.3-fold (p < 0.01) lower than that of the parental cell line. PC-9/0.5 and PC-14/1.5 cells showed a similar tendency without statistical significance. The IC50 values of other thymidylate synthase inhibitors, 5-fluoro-2'-deoxyuridine and trifluorothymidine, were lower for PC-7/1.0, PC-9/0.5 and PC-14/1.5 cells than for their parental cell lines. The mechanisms of collateral sensitivity to 5-fluorouracil were examined in PC-7/1.0 cells. Thymidylate synthase activity was determined by fluorodeoxyuridine monophosphate (FdUMP) binding activity and no consistent difference between cisplatin-resistant and parental cell lines was found. The inhibition of thymidylate synthase after exposure to 10 μg/ml of 5-fluorouracil for 6 h was higher in PC-7 (84.1%) than PC-7/1.0 (51.3%) cells. Thus, there is no direct correlation in these cell lines between the sensitivity to inhibition of thymidylate synthase by 5-fluorouracil and 5-fluorouracil cytotoxicity. Incorporation of [3H]-thymidine into DNA was lower in PC-7/1.0 compared to PC-7 cells without a significant difference in thymidine kinase activity. We speculate that the decrease in salvage synthesis of thymidylate was a possible reason for the collateral sensitivity of PC-7/1.0 cells.

Original languageEnglish
Pages (from-to)332-336
Number of pages5
JournalCancer Journal
Volume3
Issue number6
Publication statusPublished - 1990
Externally publishedYes

Fingerprint

Thymidylate Synthase
Cisplatin
Lung Neoplasms
Fluorouracil
Cell Line
Inhibitory Concentration 50
Trifluridine
Floxuridine
Thymidine Kinase
Non-Small Cell Lung Carcinoma
Thymidine
DNA

Keywords

  • cisplatin resistance
  • collateral sensitivity
  • thymidylate synthase inhibitor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Collateral sensitivity of cisplatin-resistant human lung cancer cell lines to thymidylate synthase inhibitors. / Ohe, Y.; Sugimoto, Yoshikazu; Saijo, N.

In: Cancer Journal, Vol. 3, No. 6, 1990, p. 332-336.

Research output: Contribution to journalArticle

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abstract = "The sensitivity of three cisplatin-resistant human non-small cell lung cancer cell lines, PC-7/1.0, PC-9/0.5, and PC-14/1.5 cells, to 5-fluorouracil was compared with that of the parental cell lines. The 50{\%} inhibitory concentrations (IC50) value of 5-fluorouracil for PC-7/1.0 cells was 4.3-fold (p < 0.01) lower than that of the parental cell line. PC-9/0.5 and PC-14/1.5 cells showed a similar tendency without statistical significance. The IC50 values of other thymidylate synthase inhibitors, 5-fluoro-2'-deoxyuridine and trifluorothymidine, were lower for PC-7/1.0, PC-9/0.5 and PC-14/1.5 cells than for their parental cell lines. The mechanisms of collateral sensitivity to 5-fluorouracil were examined in PC-7/1.0 cells. Thymidylate synthase activity was determined by fluorodeoxyuridine monophosphate (FdUMP) binding activity and no consistent difference between cisplatin-resistant and parental cell lines was found. The inhibition of thymidylate synthase after exposure to 10 μg/ml of 5-fluorouracil for 6 h was higher in PC-7 (84.1{\%}) than PC-7/1.0 (51.3{\%}) cells. Thus, there is no direct correlation in these cell lines between the sensitivity to inhibition of thymidylate synthase by 5-fluorouracil and 5-fluorouracil cytotoxicity. Incorporation of [3H]-thymidine into DNA was lower in PC-7/1.0 compared to PC-7 cells without a significant difference in thymidine kinase activity. We speculate that the decrease in salvage synthesis of thymidylate was a possible reason for the collateral sensitivity of PC-7/1.0 cells.",
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AB - The sensitivity of three cisplatin-resistant human non-small cell lung cancer cell lines, PC-7/1.0, PC-9/0.5, and PC-14/1.5 cells, to 5-fluorouracil was compared with that of the parental cell lines. The 50% inhibitory concentrations (IC50) value of 5-fluorouracil for PC-7/1.0 cells was 4.3-fold (p < 0.01) lower than that of the parental cell line. PC-9/0.5 and PC-14/1.5 cells showed a similar tendency without statistical significance. The IC50 values of other thymidylate synthase inhibitors, 5-fluoro-2'-deoxyuridine and trifluorothymidine, were lower for PC-7/1.0, PC-9/0.5 and PC-14/1.5 cells than for their parental cell lines. The mechanisms of collateral sensitivity to 5-fluorouracil were examined in PC-7/1.0 cells. Thymidylate synthase activity was determined by fluorodeoxyuridine monophosphate (FdUMP) binding activity and no consistent difference between cisplatin-resistant and parental cell lines was found. The inhibition of thymidylate synthase after exposure to 10 μg/ml of 5-fluorouracil for 6 h was higher in PC-7 (84.1%) than PC-7/1.0 (51.3%) cells. Thus, there is no direct correlation in these cell lines between the sensitivity to inhibition of thymidylate synthase by 5-fluorouracil and 5-fluorouracil cytotoxicity. Incorporation of [3H]-thymidine into DNA was lower in PC-7/1.0 compared to PC-7 cells without a significant difference in thymidine kinase activity. We speculate that the decrease in salvage synthesis of thymidylate was a possible reason for the collateral sensitivity of PC-7/1.0 cells.

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