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Characterization of a Human Small Cell Lung Carcinoma Cell Line with Acquired Resistance to cis-Diamminedichloroplatinum(II) in Vitro¹

Division of Medical Oncology, Department of Internal Medicine [G. A. P. H., N. H. M., E. G. E. d. V], Department of Clinical Immunology [L. d. L.], Department of Human Genetics [B. d. J.], and Pharmaceutical Department [D. R. A. U.], University Hospital, Groningen, The Netherlands; Medical Biological Laboratory T.N.O., Rijswijk, The Netherlands [A. M. J. F-S]; and Department of Pathology, Free University Amsterdam, The Netherlands [R. J. S.]

A 6.4-fold cis-diamminedichloroplatinum(II) (CDDP) resistant human small cell lung carcinoma cell line (GLC₄-CDDP) was developed to study acquired CDDP resistance in vitro. Compared to the sensitive cell line (GLC₄), the GLC₄-CDDP showed an increase in doubling time and a decrease in cloning efficiency, cellular size, double minutes per cell, cellular protein, and nuclear protein content.

While a complete cross-resistance for tetraplatin and a partial cross-resistance for doxorubicin, melphalan, cadmium chloride, carboplatin, and cis-dichloro-trans-dihydroxo-cis-bis(isoprolylamine)platinum(IV) (resistance factor, respectively, 4.0, 5.8, 2.1, 1.5, 2.9) was found, no cross-resistance for vincristine was found.

In the GLC₄-CDDP line in comparison to the GLC₄ line, glutathione and total amount of sulfhydryl compounds was significantly increased, while glutathione S-transferase and glutathione reductase was the same.

The platinum content in cells and nuclei was lower in the resistant line, but after correction for cellular protein or volume no difference was found. The amount of platinum bound to DNA was significantly lower in the GLC₄-CDDP line.

After a 1-h incubation with CDDP, the amount of Pt-GG adducts was the same and the amount of interstrand cross-links was reduced in the GLC₄-CDDP line as compared to GLC₄.

In conclusion, in the GLC₄-CDDP line the phenotype and genotype are changed and various mechanisms, such as decreased Pt-DNA binding, elevated glutathione, and reduced interstrand cross-links, play a role in the development of the CDDP resistance.

¹ This study is supported by a grant from the Dutch Cancer Foundation GUKC 86-1.

² To whom requests for reprints should be addressed, at Department of Internal Medicine, University Hospital, Oostersingel 59, 9713 EZ Groningen, The Netherlands.

Received 11/ 6/87. Revised 4/25/88. Revised 8/25/88. Accepted 9/ 1/88.

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