DNA Topoisomerase IIα in Multiple Myeloma: A Marker of Cell Proliferation and Not Drug Resistance

Abstract

DNA topoisomerase IIα (topo IIα) is the target for a number of antineoplastic agents. Down-regulation of this enzyme is one form of drug resistance. Topo IIα is also involved in DNA replication and transcription and serves as an indicator of proliferation rate in many human malignancies. This study examines whether topo IIα is one of the mechanisms of chemoresistance commonly observed in multiple myeloma (MM) or alternatively, whether topo IIα is associated with tumor cell proliferation. Bone marrow (BM) biopsy sections from 72 cases of MM, stratified according to proliferative activity (bromodeoxyuridine uptake), were immunostained for topo IIα. Immunoreactivity with an addi- tional marker of drug resistance, glutathione-S-transferase π, and the proliferation marker Ki-67 were also examined. Topo IIα was expressed in 26 (36%) cases and correlated strongly with proliferative activity (P <.001). A role for drug resistance could not be supported, given this strong relationship with proliferation and the finding that glutathione-S-transferase π expression in 57 (78%) cases was independent of topo IIα immunoreactivity. Topo IIα was identified in 91 to 100% of highly proliferative tumors, as evaluated by bromodeoxyuridine uptake or Ki-67 reactivity, respectively. Proliferation also correlated with the histologic grade of the MM. Therefore, topo IIα immunoreactivity is primarily a marker of cell proliferation in MM and as such is likely to have prognostic significance. Highly proliferative tumors are most likely to be sensitive to chemotherapeutic protocols using anti–topo IIα agents.