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

• Published in: International journal of cancer Vol. 80; no. 3; pp. 413 - 416
• Main Authors: Zoli, Wainer, Ricotti, Luca, Barzanti, Fabio, Dal Susino, Monica, Frassineti, Giovanni Luca, Milri, Carlo, Casadei Giunchi, Donata, Amadori, Dino
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 29.01.1999; Wiley-Liss
• Subjects: Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Breast Neoplasms - drug therapy; Cell Cycle - drug effects; Chemotherapy; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Doxorubicin - administration & dosage; Doxorubicin - pharmacology; Drug Administration Schedule; Drug Interactions; Female; Flow Cytometry; Humans; Medical sciences; Paclitaxel - administration & dosage; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Tumor Cells, Cultured - drug effects; Tumor Stem Cell Assay; Antineoplastic agent; Human; Cell culture; Flow cytometry; Drug combination; Carcinoma; Gemcitabine; Cytotoxicity; Malignant tumor; Doxorubicin; In vitro; Mammary gland diseases; Chemotherapy; Taxane derivatives; Dependence; Schedule; Established cell line; Paclitaxel; Anthracyclins; Drug interaction; Fluorine Organic compounds; Mammary gland; Pyrimidine nucleoside
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/(SICI)1097-0215(19990129)80:3<413::AID-IJC13>3.0.CO;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 μg/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. Int. J. Cancer 80:413–416, 1999. © 1999 Wiley‐Liss, Inc.