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Division of Hematology and Oncology, Department of Internal Medicine, Karmanos Cancer Institute [E. J. M-O., A. M. A-K., N. I. O., R. M. M.], and Cancer Biology Program, Department of Pharmacology, Wayne State University School of Medicine [H-Y. W.], Detroit, Michigan 48201

Topoisomerase (Topo) II has proven to be an adequate anticancer target for tumors expressing this enzyme. In this study, we elucidated the effect of 2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic acid (XK469; a new Topo IIß inhibitor) in the modulation of Topo II levels and sensitivity to Topo II poisons. We demonstrate by Western blot analysis that indolent B-cell tumors express undetectable levels of this enzyme and are refractory to the effects of Topo II poisons such as VP16. Using the Waldenstrom’s macroglobulinemia (WM) cell line WSU-WM, we show that XK469 induced the expression of Topo II protein by 24 h compared with control. Immunofluorescence studies by confocal microscopy using a specific monoclonal antibody against Topo II supported the immunoblot findings with high intensity staining in XK469-exposed cells. To determine the effect of up-regulating Topo II on sensitivity of Topo II-directed inhibitors, WSU-WM cells were exposed to simultaneous, sequential, and reverse order XK469 and VP16. We demonstrate that 24 h of exposure to XK469 before VP16 resulted in a maximum synergistic response. In contrast, simultaneous or reverse order exposure resulted in an antagonistic effect. A similar trend was observed with cells obtained from chronic lymphocytic leukemia patients, but not in normal lymphocytes. This increase in VP16 sensitivity after 24 h of XK469 exposure was associated with VP16-dependent DNA cleavage, as demonstrated by formation of a smeared DNA band in a SDS-KCL DNA cleavage assay. From this study, we concluded that XK469 up-regulates Topo II levels and consequently sensitizes indolent malignant B cells to the cytotoxic effect of VP16 in a schedule-dependent manner.

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				E. J. Mensah-Osman, A. M. Al-Katib, and R. M. Mohammad Preclinical Evaluation of 2-[4-(7-Chloro-2-quinoxalinyloxy)phenoxy]-propionic Acid as a Modulator of Etoposide in Human Waldenstrom's Macroglobulinemia Xenograft Model Clin. Cancer Res., November 15, 2003; 9(15): 5794 - 5797. [Abstract] [Full Text] [PDF]