Characterisation of a human small-cell lung cancer cell line resistant to the DNA topoisomerase I-directed drug topotecan

Br J Cancer. 1995 Aug;72(2):399-404. doi: 10.1038/bjc.1995.345.


Camptothecins are DNA topoisomerase I-directed anti-tumour drugs with a novel mechanism of action. Topotecan (TPT), a hydrophilic derivative of camptothecin, is currently undergoing phase II clinical trials in small-cell lung cancer (SCLC). Human SCLC OC-NYH cells were made more than 6-fold resistant to topotecan by stepwise drug exposure and resistance was stable for 70 passages without drug. NYH/TPT cells had half the topoisomerase I level and activity of wild-type cells. However, no difference in camptothecin or topotecan inhibition of topoisomerase I-mediated DNA relaxation was found, indicating that the enzyme itself was unchanged in the resistant cell. In NYH/TPT cells, topoisomerase II alpha and beta levels were increased approximately 2-fold. Accordingly, the topoisomerase II-directed drug etoposide (VP-16) induced an increased number of DNA single-strand breaks in NYH/TPT cells. However, sensitivity to different topoisomerase II-targeting agents in NYH/TPT cells varied from increased to decreased, indicating a role for as yet unidentified factors acting on the pathway to cell death after topoisomerase II-induced DNA damage has occurred. Of 20 anti-cancer agents tested, only hydroxyurea showed marked collateral hypersensitivity in NYH/TPT cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacokinetics
  • Camptothecin / pharmacology
  • Carbon Radioisotopes
  • Carcinoma, Small Cell / drug therapy*
  • Carcinoma, Small Cell / enzymology
  • DNA Damage
  • DNA Topoisomerases, Type I / metabolism
  • DNA Topoisomerases, Type II* / analysis
  • DNA-Binding Proteins
  • Drug Resistance
  • Drug Screening Assays, Antitumor
  • Humans
  • Isoenzymes / analysis
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Topoisomerase I Inhibitors*
  • Topotecan
  • Tumor Cells, Cultured / drug effects*


  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Carbon Radioisotopes
  • DNA-Binding Proteins
  • Isoenzymes
  • Topoisomerase I Inhibitors
  • Topotecan
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II
  • Camptothecin