Human DNA topoisomerase I: An anticancer drug target present in human sarcomas.
New anticancer drugs targeting DNA topoisomerase I (topo I) are showing activity against human sarcomas. Laboratory studies have indicated that cells responsive to topo I-targeted drugs have elevated levels of topo I, require active DNA replication, and may require a functional apoptotic pathway. In this study, we evaluated these potential markers of topo I-targeted drug sensitivity in 55 cases of human sarcoma (42 high grade, 4 intermediate grade, and 9 low grade). By immunohistochemical staining, we observed elevated topo I expression in 20 of 55 neoplasms (36%). Immunohistochemical staining for the proliferation marker DNA topoisomerase II-alpha (topo II-alpha), showed that 15 of 55 neoplasms (27%) had topo II-alpha indices >50, indicating a large number of actively cycling tumor cells. Abnormal p53 expression was observed in 19 of the 55 cases (35%). None of the cases were interpreted as positive for ALK-1. To complement our immunohistochemical staining of topo I, we isolated functionally active topo I from extracts of a human sarcoma. These isolates demonstrated that sarcoma topo I is sensitive to topo I-targeted anticancer drugs. Of the 55 cases of human sarcoma, 7 (13%) had high levels of topo I, a large number of cycling tumor cells, and normal p53 expression. These are the molecular parameters that might suggest responsiveness to drugs targeting topo I.
Coleman
Landon W
LW
Department of Pathology, University of Utah Health Sciences Center, Salt Lake City 84132, USA.
Rohr
L Ralph
LR
Bronstein
Igor B
IB
Holden
Joseph A
JA
D030201:Activin Receptors, Type I / Q000096:biosynthesis; D030301:Activin Receptors, Type II; D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis*; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy* / Q000201:enzymology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II