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 LIa5μM 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 LIa5μM but not L1210 cells. These agents also selectively increased the formation of breaks in the DNA of LIa5μM but not L1210 cells. The DNA unknotting assay with phage P4 DNA indicated equivalent DNA type II topoisomerase activity in nuclear extracts of LIa5μM and L1210 cells. The factor that reduced the formation of breaks in cellular LIa5μM DNA by VM-26 provided less protection against equitoxic levels of doxorubicin, to which LIa5μM cells are crossresistant.
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This work was supported by Research Project Grant CA 39426 and Cancer Center Support (Core) Grant CA 21765 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities
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Roberts, D., Foglesong, P.D., Parganas, E. et al. Reduced formation of lesions in the DNA of a multidrug-resistant L1210 subline selected for teniposide resistance. Cancer Chemother. Pharmacol. 23, 161–168 (1989). https://doi.org/10.1007/BF00267948
- Cellular Level
- Multidrug Resistance