Mechanisms of collateral sensitivity to fluorouracil of a cis-diamminedichloroplatinum(II)-resistant human non-small lung cancer cell line

Yoshikazu Sugimoto, Y. Ohe, K. Nishio, T. Ohmori, T. Morikage, Y. Fujiwara, N. Saijo

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)857-864
Number of pages8
JournalBritish Journal of Cancer
Volume65
Issue number6
Publication statusPublished - 1992
Externally publishedYes

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Fluorouracil
Cisplatin
Lung Neoplasms
Cell Line
Deoxyribonucleotides
Vinca Alkaloids
Thymidylate Synthase
Anthracyclines
Bleomycin
Mitomycin
Etoposide
Phosphotransferases
RNA
thymidine 5'-triphosphate
DNA
Serum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mechanisms of collateral sensitivity to fluorouracil of a cis-diamminedichloroplatinum(II)-resistant human non-small lung cancer cell line. / Sugimoto, Yoshikazu; Ohe, Y.; Nishio, K.; Ohmori, T.; Morikage, T.; Fujiwara, Y.; Saijo, N.

In: British Journal of Cancer, Vol. 65, No. 6, 1992, p. 857-864.

Research output: Contribution to journalArticle

Sugimoto, Yoshikazu ; Ohe, Y. ; Nishio, K. ; Ohmori, T. ; Morikage, T. ; Fujiwara, Y. ; Saijo, N. / Mechanisms of collateral sensitivity to fluorouracil of a cis-diamminedichloroplatinum(II)-resistant human non-small lung cancer cell line. In: British Journal of Cancer. 1992 ; Vol. 65, No. 6. pp. 857-864.
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abstract = "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.",
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AU - Ohmori, T.

AU - Morikage, T.

AU - Fujiwara, Y.

AU - Saijo, N.

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