Schedule-dependent interaction of doxorubicin, paclitaxel and gemcitabine in human breast cancer cell lines

Int J Cancer. 1999 Jan 29;80(3):413-6. doi: 10.1002/(sici)1097-0215(19990129)80:3<413::aid-ijc13>;2-i.


We showed previously that a sequential treatment with doxorubicin (4 hr) followed by paclitaxel (24 hr) (Dox-->Pacl) induces a synergistic cytotoxic effect in the BRC-230 breast cancer cell line and in human primary breast cancer cultures. The validity of this experimental finding was confirmed in a clinical phase I/II study on advanced breast cancer patients. To improve the cytotoxic effect obtained by the Dox-->Pacl sequence, we analyzed the effect of adding gemcitabine (Gem) to the Dox-->Pacl sequence in a preclinical study. Our study was performed on BRC-230 and MCF-7 cell lines, and cytotoxic activity was evaluated by the sulforhodamine B assay and the type of drug interaction by Drewinko's test. When Gem (0.01 microg/ml for 24 hr) was given immediately or 24 hr after Dox-->Pacl, an antagonistic cytotoxic effect was observed. Conversely, a synergistic effect was found when Gem was given 48 hr after Dox-->Pacl. From results of flow cytometric analysis, the synergistic effect was attributed to cell cycle perturbation. Cells were arrested in G2-M (95% in treated vs. 21% in control samples) 24 hr after Dox-->Pacl treatment. The block progressively recovered thereafter, and after a further 24 hr, at the time of Gem treatment, the cells progressed into the G1-S phase boundary (the cell cycle phase susceptible to the cytocidal effect of the drug). Our findings suggest that the interactions of Dox, Pacl and Gem are highly schedule- and time-dependent and should be taken into consideration in the planning of clinical protocols.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Cell Cycle / drug effects
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Doxorubicin / administration & dosage
  • Doxorubicin / pharmacology
  • Drug Administration Schedule
  • Drug Interactions
  • Female
  • Flow Cytometry
  • Humans
  • Paclitaxel / administration & dosage
  • Paclitaxel / pharmacology
  • Tumor Cells, Cultured / drug effects
  • Tumor Stem Cell Assay


  • Deoxycytidine
  • Doxorubicin
  • gemcitabine
  • Paclitaxel