Antiproliferative activity of the topoisomerase I inhibitors topotecan and camptothecin, on sub- and postconfluent tumor cell cultures

Paulo E. Pizao, Evelien Smitskamp-Wilms, Jannette Van Ark-Otte, Jos H. Beijnen, Godefridus J. Peters, Herbert M. Pinedo, Giuseppe Giaccone

Research output: Contribution to journalArticlepeer-review


We have assessed the antiproliferative effects of a 24-hr exposure to the topoisomerase I inhibitors, topotecan and camptothecin, on two colon and one ovarian human tumor cell lines, cultured as subconfluent and as multilayered postconfluent cultures. Chemosensitivity was measured by the sulforhodamine B assay. In general, postconfluent cultures were less sensitive to these agents, yielding gi50s (drug concentrations inhibiting growth by 50%) from 1.2 to more than 6000 times higher than those of subconfluent cultures. Both compounds displayed similar effects on subconfluent cells, inducing complete growth inhibition at concentrations ranging from 0.03 to 0.5 μM. Topotecan, however, was more potent than camptothecin in two out of the three cell lines tested as multilayered postconfluent cultures. Topoisomerase I mRNA expression on postconfluent cultures was 50% lower than on subconfluent cultures in the three cell lines studied. However, we did not detect any reproducible differences in topoisomerase I protein expression and in relaxation activity of supercoiled DNA between the two types of cultures. From accumulation experiments it appeared that the peak concentration of the lactone form of topotecan as well as the area under the concentration-time curve (AUC) were 2-fold higher in the monolayer than in the multilayer cultures. Therefore, the differences in the activity of topoisomerase I inhibitors under our experimental conditions were likely due to a decreased rate of proliferation of postconfluent cells, associated with a reduction in drug uptake.

Original languageEnglish (US)
Pages (from-to)1145-1154
Number of pages10
JournalBiochemical Pharmacology
Issue number6
StatePublished - Sep 15 1994
Externally publishedYes


  • camptothecin
  • cytotoxicity
  • gene expression
  • postconfluent cultures
  • topoisomerase I
  • topotecan

ASJC Scopus subject areas

  • Pharmacology


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