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

A 6.4-fold ciVdiammincdidili>riiplutimini( 11) (CDDP) resistant human small cell lung carcinoma cell line (GLG-CDDP) was developed to studyacquired 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 crossresistance for doxorubicin, melphalan, cadmium chloride, carboplatin, and c»-dichloro-trans-dihydroxo-c»-bis(isoprolylamine)platinum(IV) (resistance factor, respectively, 4.0,5.8,2.1,1.5,2.9) was found, no crossresistance for vincristine was found. In the GLCi-CDDP line in comparison to the GLQ line, glutathione and total amount of sulfhydryl compounds was significantly increased, while glutathione 5-transferase and glutathione reducÃ-asewas 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 GLQ-CDDP line. After a l-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 GIX '4. 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.