Reduced formation of lesions in the DNA of a multidrug-resistant L1210 subline selected for teniposide resistance

Abstract

Earlier studies have suggested that higher cellular levels of teniposide (VM-26) are required for the inhibition of growth in L1210/VM-26 sublines than in parental L1210 cells. On the basis of this observation, we hypothesized that resistance to VM-26, which is partly attributed to multidrug resistance, also resulted in reduced formation of DNA lesions by the drug. In confirmation of this hypothesis, equitoxic concentrations of VM-26 produced fewer breaks in the DNA of LIa5 microM cells, the prototype L1210/VM-26 subline, than in that of L1210 cells. Previously, potassium cyanide (KCN) and verapamil were shown to increase the levels of VM-26 in LIa5 microM but not L1210 cells. These agents also selectively increased the formation of breaks in the DNA of LIa5 microM but not L1210 cells. The DNA unknotting assay with phage P4 DNA indicated equivalent DNA type II topoisomerase activity in nuclear extracts of LIa5 microM and L1210 cells. The factor that reduced the formation of breaks in cellular LIa5 microM DNA by VM-26 provided less protection against equitoxic levels of doxorubicin, to which LIa5 microM cells are cross-resistant.