Research in our laboratory has focused on defining the mechanisms of drug resistance to inhibitors of mammalian DNA topoisomerase I, II alpha, and II beta. These enzymes are the targets of several commonly used anti-tumor agents, including etoposide, doxorubicin, mitoxantrone, topotecan and irinotecan. Recently, we have found that the trafficking of topoisomerase I and/or II to the cytoplasm is a mechanism of cellular drug resistance that can occur in the absence of drug exposure. Defining the nuclear export signal of topoisomerase II alpha is a current project in the laboratory. Our lab is also involved in several translational research studies, which aim to define the role of quantitative and qualitative alterations in topoisomerases in determining cellular sensitivity to topoisomerase inhibitors in vivo.. Thus, tumor biopsies from patients with multiple myeloma, AML, non-Hodgkin's lymphoma, small cell lung cancer, rectal carcinoma, and malignant melanoma are currently being examined for this purpose.