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Metallothionein Content Correlates with the Sensitivity of Human Small Cell Lung Cancer Cell Lines to Cisplatin¹

Pharmacology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104 [K. K., Y. F., K. N., T. O., Y. S., N. S.] Department of Radiopharmacy, Hoshi University, 4-41, Ebara 2-chome, Shinagawa-ku, Tokyo, 142 [K. K.]; and third Internal Medicine, School of Medicine, Kanazawa University, Takaramachi 13-1, Kanazawa, 920 [K. K., T. M.], Japan

We have established cis-diamminedichloroplatinum(II) (cisplatin) resistant human small cell lung cancer cell lines, H69/CDDP_0.2 and H69/CDDP, to investigate the mechanism of acquired resistance to cisplatin. H69/CDDP_0.2 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 cross-link formations, determined by filter elution assay in H69/CDDP_0.2 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/CDDP_0.2, 12 nmol/min/mg protein; H69/CDDP, 74 nmol/min/mg protein, respectively) and an overexpression of glutathione S-transferase 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 , but this did not alter the relative degree of resistance. Intracellular metallothionein content (H69, 14 pmol/mg protein, H69/CDDP_0.2, 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.

¹ This research was supported in part by a Grant-in-Aid from the Ministry of Health and Welfare for the Comprehensive 10-Year Strategy for Cancer Control.

² Recipient of a research resident fellowship from the Foundation for Promotion of Cancer Research.

³ To whom requests for reprints should be addressed.

Received 11/27/90. Accepted 4/ 9/91.

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