OBJECTIVE Topoisomerase II alpha content, topoisomerase II catalytic activity and drug sensitivities to the topoisomerase II inhibitors, doxorubicin and etoposide, were examined in a panel of 14 unselected human lung cancer cell lines in order to determine the relationship between topoisomerase II and drug sensitivities to the topoisomerase II inhibitors. METHODS Drug sensitivities were determined using a microculture tetrazolium assay. The topoisomerase II alpha levels were determined by Western blot analysis and the topoisomerase II catalytic activity was determined using a decatenation assay of kinetoplast DNA, using nuclear protein from cells of each cell line. RESULTS Drug sensitivity tests revealed that small-cell lung cancer (SCLC) cell lines were more sensitive to drugs than non-small-cell lung cancer (NSCLC) cell lines. The relative topoisomerase II alpha levels and relative topoisomerase II catalytic activity from SCLC cell lines (mean +/- SD 0.89 +/- 0.54 and 5.3 +/- 3.4, respectively) were slightly higher than those from NSCLC cell lines (0.78 +/- 0.56 and 4.0 +/- 2.8, respectively), but the differences were not statistically significant, and not sufficient to account for the variation in drug sensitivities. Moreover, no clear association was observed between the topoisomerase II alpha levels or the topoisomerase II catalytic activity and drug sensitivities in the cell lines studied. CONCLUSIONS These findings suggest that the difference in drug sensitivities to doxorubicin and etoposide in human lung cancer cell lines might not be explainable by the topoisomerase II alpha levels and topoisomerase II catalytic activity. Moreover, our results suggest that the topoisomerase II alpha levels and topoisomerase II catalytic activity may play a minor role in the determination of clinical drug resistance of human lung cancers.