Synergistic interaction between topotecan and microtubule-interfering agents.
OBJECTIVE
Topotecan is a topoisomerase I inhibitor with demonstrated anticancer activity in preclinical and clinical studies. The purpose of the present study was to evaluate drug-drug interactions in therapeutic regimens that would combine topotecan with microtubule-interfering agents, such as Taxol and vinblastine.


METHODS
The cytotoxic activities of various drug combinations and schedules of administration were measured in a colon cancer cell line using the MTT assay. Western blot and flow cytometry were performed to determine the effects of Taxol and vinblastine on topoisomerase I and Bcl-xL protein levels and cell cycle distribution.


RESULTS
Brief incubation of colon cancer cells with low concentrations of either Taxol or vinblastine increased the efficacy of a subsequent treatment with topotecan. Preincubation of cells with vinblastine or Taxol reduced by 10- to 40-fold the concentration of topotecan necessary to induce a 50% decrease in cell survival. The effects were maximal when the cells were treated for 5 h with microtubule-interfering agents and then incubated for 19 h in drug-free medium before the addition of topotecan. Under these conditions, both Taxol and vinblastine caused an increase in topoisomerase I protein levels, fraction of S phase cells, and extent of Bcl-xL phosphorylation immediately prior to the addition of topotecan. All these factors may contribute to the increased efficacy of topotecan observed with sequential therapy.


CONCLUSIONS
Combinations of topotecan and microtubule-interfering agents result in synergistic anticancer activity when the drugs are administered sequentially. The promising preclinical data presented here encourage clinical testing of these drug combinations using a sequential schedule of administration.
Bahadori
H R
HR
Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston 29425, USA.
Green
M R
MR
Catapano
C V
CV
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005562:Formazans; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013778:Tetrazolium Salts; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism; D014747:Vinblastine / Q000494:pharmacology*; D051020:bcl-X Protein
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; D004791:Enzyme Inhibitors; D005562:Formazans; D019253:Proto-Oncogene Proteins c-bcl-2; D013778:Tetrazolium Salts; D059004:Topoisomerase I Inhibitors; D051020:bcl-X Protein; C079782:MTT formazan; D014747:Vinblastine; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; D017239:Paclitaxel