Elevations of DNA topoisomerase I catalytic activity and immunoprotein in human malignancies.
DNA topoisomerase I (topo I) is the molecular target for the camptothecin group of anticancer drugs. These drugs are showing activity against a wide array of human tumors. Many data have indicated that the sensitivity of a tumor cell to the camptothecins is dependent on tumor topo I levels. Drug-sensitive cells have high levels of topo I. Unfortunately, there is still a relative lack of information on topo I levels in human malignancies. Because of this, we investigated topo I activity and immunoprotein levels in a variety of normal murine and human tissues, as well as tissues obtained from several carcinomas, lymphomas, and sarcomas. Flow cytometric analysis was also performed on the neoplastic specimens to determine the percentage of cycling cells. Topo I catalytic activity was detected in all normal tissues at a fairly constant level. The average topo I catalytic activity in normal mammalian tissues 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 malignancies and ranged from a low of 1.4 x 10(4) units/mg protein in a rhabdomyosarcoma to a high of 160 x 10(4) units/mg protein in a poorly differentiated ovarian carcinoma. Western blot analysis with either a mouse monoclonal antibody or scleroderma antibodies directed against topo I revealed that the elevated topo I catalytic activity levels in the malignant tissues are due to elevated amounts of topo I immunoprotein. It is possible that the high topo I levels that characterize several different types of human malignancies might indicate that these tumors would be sensitive to many of the new drugs that target topo I.
Bronstein
I B
IB
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
Vorobyev
S
S
Timofeev
A
A
Jolles
C J
CJ
Alder
S L
SL
Holden
J A
JA
D000818:Animals; D015153:Blotting, Western; D002277:Carcinoma / Q000201:enzymology / Q000276:immunology; D004264:DNA Topoisomerases, Type I / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008223:Lymphoma / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology*; D012509:Sarcoma / Q000201:enzymology / Q000276:immunology
D004264:DNA Topoisomerases, Type I