Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin

Kazuo Kasahara, Yasuhiro Fujiwar, Kazuto Nishio, Tohru Ohmori, Yoshikazu Sugimoto, Kazuhide Komiya, Tamotsu Matsuda, Nagahiro Saijo

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Abstract

We have established cis-diamminedichloroplatinum(II) (cisplatin) resistant human small cell lung cancer cell lines, H69/CDDP0.2 and H69/ CDDP, to investigate the mechanism of acquired resistance to cisplatin. H69/CDDP0.2 and H69/CDDP were 6- and 11-fold resistant to cisplatin compared with the H69 parental cell line. H69/CDDP was also resistant to cadmium chloride (2-fold), cis-diammine(glycolato)platinum (4-fold), 4-hydroperoxycyclophosphamide (3-fold) and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (4-fold) if the drug concentrations that inhibit cell growth by 50% from growth inhibition assay were compared. There was no significant difference in the cisplatin accumulation among these cell lines. Although DNA interstrand crosslink formations, determined by filter elution assay in H69/CDDP0.2 and H69/CDDP, was decreased to 20 to 30% of that in H69 parental cells, the repair capacity of DNA interstrand cross-links was equivalent in all three cell lines. Intracellular glutathione content was equal in all cell lines. H69/CDDP had the highest glutathione S-transferase activity (H69, 11 nmol/min/mg protein, H69/CDDP0.2, 12 nmol/min/mg protein; H69/CDDP, 74 nmol/min/mg protein, respectively) and an overexpression of glutathione S-transferase π mRNA. The drug concentrations that inhibit cell growth by 50% for cisplatin in all cell lines were decreased by treatment with ethacrynic acid, an inhibitor of glutathione S-transferase π, but this did not alter the relative degree of resistance. Intracellular metallothionein content (H69, 14 pmol/mg protein, H69/CDDP0.2, 22 pmol/mg protein; H69/CDDP, 33 pmol/mg protein, respectively) and expression of metallothionein mRNA were correlated with the drug concentrations that inhibit cell growth by 50% of the three cell lines for cisplatin and cadmium chloride. The present study suggested the importance of metallothionein in the mechanisms of cisplatin resistance.

Original languageEnglish
Pages (from-to)3237-3242
Number of pages6
JournalCancer Research
Volume51
Issue number12
Publication statusPublished - 1991 Jun 15
Externally publishedYes

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Metallothionein
Small Cell Lung Carcinoma
Cisplatin
Cell Line
Glutathione Transferase
Cadmium Chloride
Proteins
perfosfamide
Growth
Pharmaceutical Preparations
Ethacrynic Acid
Messenger RNA
Platinum
DNA Repair
Glutathione
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kasahara, K., Fujiwar, Y., Nishio, K., Ohmori, T., Sugimoto, Y., Komiya, K., ... Saijo, N. (1991). Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. Cancer Research, 51(12), 3237-3242.

Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. / Kasahara, Kazuo; Fujiwar, Yasuhiro; Nishio, Kazuto; Ohmori, Tohru; Sugimoto, Yoshikazu; Komiya, Kazuhide; Matsuda, Tamotsu; Saijo, Nagahiro.

In: Cancer Research, Vol. 51, No. 12, 15.06.1991, p. 3237-3242.

Research output: Contribution to journalArticle

Kasahara, K, Fujiwar, Y, Nishio, K, Ohmori, T, Sugimoto, Y, Komiya, K, Matsuda, T & Saijo, N 1991, 'Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin', Cancer Research, vol. 51, no. 12, pp. 3237-3242.
Kasahara K, Fujiwar Y, Nishio K, Ohmori T, Sugimoto Y, Komiya K et al. Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. Cancer Research. 1991 Jun 15;51(12):3237-3242.
Kasahara, Kazuo ; Fujiwar, Yasuhiro ; Nishio, Kazuto ; Ohmori, Tohru ; Sugimoto, Yoshikazu ; Komiya, Kazuhide ; Matsuda, Tamotsu ; Saijo, Nagahiro. / Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. In: Cancer Research. 1991 ; Vol. 51, No. 12. pp. 3237-3242.
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abstract = "We have established cis-diamminedichloroplatinum(II) (cisplatin) resistant human small cell lung cancer cell lines, H69/CDDP0.2 and H69/ CDDP, to investigate the mechanism of acquired resistance to cisplatin. H69/CDDP0.2 and H69/CDDP were 6- and 11-fold resistant to cisplatin compared with the H69 parental cell line. H69/CDDP was also resistant to cadmium chloride (2-fold), cis-diammine(glycolato)platinum (4-fold), 4-hydroperoxycyclophosphamide (3-fold) and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (4-fold) if the drug concentrations that inhibit cell growth by 50{\%} from growth inhibition assay were compared. There was no significant difference in the cisplatin accumulation among these cell lines. Although DNA interstrand crosslink formations, determined by filter elution assay in H69/CDDP0.2 and H69/CDDP, was decreased to 20 to 30{\%} of that in H69 parental cells, the repair capacity of DNA interstrand cross-links was equivalent in all three cell lines. Intracellular glutathione content was equal in all cell lines. H69/CDDP had the highest glutathione S-transferase activity (H69, 11 nmol/min/mg protein, H69/CDDP0.2, 12 nmol/min/mg protein; H69/CDDP, 74 nmol/min/mg protein, respectively) and an overexpression of glutathione S-transferase π mRNA. The drug concentrations that inhibit cell growth by 50{\%} for cisplatin in all cell lines were decreased by treatment with ethacrynic acid, an inhibitor of glutathione S-transferase π, but this did not alter the relative degree of resistance. Intracellular metallothionein content (H69, 14 pmol/mg protein, H69/CDDP0.2, 22 pmol/mg protein; H69/CDDP, 33 pmol/mg protein, respectively) and expression of metallothionein mRNA were correlated with the drug concentrations that inhibit cell growth by 50{\%} of the three cell lines for cisplatin and cadmium chloride. The present study suggested the importance of metallothionein in the mechanisms of cisplatin resistance.",
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N2 - We have established cis-diamminedichloroplatinum(II) (cisplatin) resistant human small cell lung cancer cell lines, H69/CDDP0.2 and H69/ CDDP, to investigate the mechanism of acquired resistance to cisplatin. H69/CDDP0.2 and H69/CDDP were 6- and 11-fold resistant to cisplatin compared with the H69 parental cell line. H69/CDDP was also resistant to cadmium chloride (2-fold), cis-diammine(glycolato)platinum (4-fold), 4-hydroperoxycyclophosphamide (3-fold) and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (4-fold) if the drug concentrations that inhibit cell growth by 50% from growth inhibition assay were compared. There was no significant difference in the cisplatin accumulation among these cell lines. Although DNA interstrand crosslink formations, determined by filter elution assay in H69/CDDP0.2 and H69/CDDP, was decreased to 20 to 30% of that in H69 parental cells, the repair capacity of DNA interstrand cross-links was equivalent in all three cell lines. Intracellular glutathione content was equal in all cell lines. H69/CDDP had the highest glutathione S-transferase activity (H69, 11 nmol/min/mg protein, H69/CDDP0.2, 12 nmol/min/mg protein; H69/CDDP, 74 nmol/min/mg protein, respectively) and an overexpression of glutathione S-transferase π mRNA. The drug concentrations that inhibit cell growth by 50% for cisplatin in all cell lines were decreased by treatment with ethacrynic acid, an inhibitor of glutathione S-transferase π, but this did not alter the relative degree of resistance. Intracellular metallothionein content (H69, 14 pmol/mg protein, H69/CDDP0.2, 22 pmol/mg protein; H69/CDDP, 33 pmol/mg protein, respectively) and expression of metallothionein mRNA were correlated with the drug concentrations that inhibit cell growth by 50% of the three cell lines for cisplatin and cadmium chloride. The present study suggested the importance of metallothionein in the mechanisms of cisplatin resistance.

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