Human DNA topoisomerase I: An anticancer drug target present in human sarcomas

Hum Pathol. 2002 Jun;33(6):599-607. doi: 10.1053/hupa.2002.124911.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / biosynthesis
  • Activin Receptors, Type II
  • Adult
  • Aged
  • Animals
  • Antibodies, Monoclonal
  • Antigens, Neoplasm
  • Antineoplastic Agents / therapeutic use*
  • DNA Topoisomerases, Type I / biosynthesis*
  • DNA Topoisomerases, Type II / biosynthesis
  • DNA-Binding Proteins
  • Female
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Sarcoma / drug therapy*
  • Sarcoma / enzymology*
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Antibodies, Monoclonal
  • Antigens, Neoplasm
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Tumor Suppressor Protein p53
  • ACVRL1 protein, human
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • Acvrl1 protein, mouse
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II