TOPOISOMERASE-II LEVELS AND DRUG RESPONSE IN SMALL-CELL LUNG-CANCER

Acquired resistance to chemotherapy is the major obstacle to cure of s mall cell lung cancer (SCLC). Some of the most active drugs in the tre atment of this tumor exert their cytotoxicity by interacting with the nuclear enzyme topoisomerase II (topo II), which in mammalian cells oc curs in two isoforms, alpha and beta. We examined the relationship bet ween levels of topo II alpha and beta and drug response in a panel of 25 unselected SCLC cell lines. Chemosensitivity to several topo II-int eractive drugs, as well as other chemotherapeutic agents, was quantita ted previously using a modified MTT assay. Topo II levels were determi ned by immunoblot analysis of whole cell lysates, with topo II alpha a nd beta isoform-specific antibodies, and results were expressed relati ve to levels found in NCI-H209 cells which had the highest topo II alp ha in this series of cell lines. Levels of topo II alpha and beta mRNA were determined by Northern blotting. Pearson correlation analysis wa s used to determine the significance of the relationship between topo II alpha and beta levels and response to the various chemotherapeutic drugs, as well as the treatment history of the patients from whom the cell lines were derived. These analyses revealed an inverse correlatio n between topo II alpha levels and resistance to all of the tested dru gs, including several drugs which are not known to interact with topo II. This correlation was statistically significant for doxorubicin, ci splatin, epirubicin, melphalan, nitrogen mustard, and vinblastine. Wit h one exception (cisplatin), there were no significant correlations be tween topo II beta levels and drug response. There was no significant correlation between topo II alpha and beta levels and treatment histor y. Taken together, our results are consistent with the hypothesis that levels of topo II alpha are important determinants of drug response i n SCLC.