ELEVATIONS OF DNA TOPOISOMERASE-I CATALYTIC ACTIVITY AND IMMUNOPROTEIN IN HUMAN MALIGNANCIES

DNA topoisomerase I (topo I) is the molecular target for the camptothe cin group of anticancer drugs. These drugs are showing activity agains t a wide array of human tumors. Many data have indicated that the sens itivity of a tumor cell to the camptothecins is dependent on tumor top o I levels. Drug-sensitive cells have high levels of topo I. Unfortuna tely, there is still a relative lack of information on topo I levels i n human malignancies. Because of this, we investigated topo I activity and immunoprotein levels in a variety of normal murine and human tiss ues, as well as tissues obtained from several carcinomas, lymphomas, a nd sarcomas. Flow cytometric analysis was also performed on the neopla stic specimens to determine the percentage of cycling cells. Topo I ca talytic activity was detected in all normal tissues at a fairly consta nt level. The average topo I catalytic activity in normal mammalian ti ssues was 2.7 +/- 1.3 x 10(4) units/mg protein (range 1.1 to 5.0 x 10( 4)). Topo I catalytic activity was much more variable in human maligna ncies and ranged from a low of 1.4 x 10(4) units/mg protein in a rhabd omyosarcoma to a high of 160 x 10(4) units/mg protein in a poorly diff erentiated ovarian carcinoma. Western blot analysis with either a mous e monoclonal antibody or scleroderma antibodies directed against topo I revealed that the elevated topo I catalytic activity levels in the m alignant tissues are due to elevated amounts of topo I immunoprotein. It is possible that the high topo I levels that characterize several d ifferent types of human malignancies might indicate that these tumors would be sensitive to many of the new drugs that target topo I.