Cytotoxic activity of topoisomerase II inhibitors in primary cultures of tumor cells from patients with human hematologic and solid tumors.

Abstract

Little is known about the in vitro activity and cross-resistance patterns of topoisomerase II (topo II) inhibitors in primary cultures of tumor cells from patients with different diagnoses. The in vitro activity of the topo II inhibitors daunorubicin, doxorubicin, idarubicin, epirubicin, amsacrine, mitoxantrone, and etoposide was determined using the fluorometric microculture cytotoxicity assay. Four hundred seventy-six samples from patients with various diagnoses were tested with continuous drug exposure. Hematologic samples were more sensitive than solid tumors to all tested drugs. Etoposide was the most active drug in solid tumors followed by epirubicin, with amsacrine the least active. The anthracyclines doxorubicin, daunorubicin, and epirubicin showed similar in vitro activity. Conversely, idarubicin showed low to moderate cross-resistance with all tested topo II inhibitors. Mitoxantrone and amsacrine showed high in vitro activity and displayed cross-resistance to the anthracyclines in the hematologic neoplasms. In the solid tumor group, mitoxantrone and amsacrine had lower activity and weak correlations with the anthracyclines. Etoposide had intermediate to weak correlations with the other drugs. There is a marked difference in tumor-type specificity and cross resistance patterns among the different topo II inhibitors tested. This may indicate that minor differences in topo II interaction and/or other mechanisms of drug action may substantially determine the cytotoxic activity of topo II-targeted drugs.