Multifactorial drug resistance in an adriamycin-resistant human small cell lung carcinoma cell line

Abstract

In a human small cell lung carcinoma cell line, GLC4, Adriamycin (ADR) resistance was induced. In the resistant cell line, GLC4/ADR, a 45% decreased intracellular ADR level was found compared to GLC4, but this could not fully explain the resistance. Evaluation of DNA damage in both cell lines after incubation with ADR by alkaline and neutral elution revealed single-strand breaks, DNA-protein cross-links, and double-strand breaks (DSB). At all incubation concentrations there was a decreased amount of all types of DNA damage in GLC4/ADR. The number of DSB was decreased also when corrected for the decreased intracellular concentration. This can at least partly be explained by the decreased stability of ADR induced DSB. After removal of ADR, 80% of DSB was repaired in 1 h in GLC4/ADR against no repair in GLC4. X-ray induced DSBs were also repaired faster: in GLC4/ADR t1/2 = 10 min and in GLC4 t1/2 = 23 min. Ratios for single strand breaks/DSBs and single strand breaks/DNA-protein cross-links between GLC4 and GLC4/ADR after exposure to ADR differed; these differences were compatible with differences in the distribution of the various types of DNA damage induced in the cell lines due to an altered ADR-topoisomerase II interaction. In this human small cell lung carcinoma cell line the resistance is multifactorial with decreased intracellular ADR levels, increased DNA repair, and altered ADR-topoisomerase interaction.