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

Abstract

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.

Nongenotoxic p53 Activation Protects Cells against S-Phase–Specific Chemotherapy

“…This is of special relevance about tumor cells with WT p53 (e.g., when gemcitabine application follows the administration of a drug that blocks cell cycle progression). Indeed, gemcitabine efficacy was decreased when administered immediately after a doxorubicin-paclitaxel combination but re-established when pretreated cells were first allowed to enter S phase (15). Thus, especially when treating tumors with a WT p53 status using drug combinations, premature cell cycle arrest should be avoided to ensure the efficacy of nucleoside analogues.…”

Phase II study of liposomal doxorubicin and gemcitabine in the salvage treatment of ovarian cancer

“…Based on in vitro data suggesting a potential synergistic interaction between the two drugs (Zoli et al, 1999;Chow et al, 2000), specific tests in preclinical models are ongoing in our laboratories in order to analyse the antitumour activity of the GEM/PLD combination and possibly clarify the underlying mechanisms of drug interaction.…”

“…The use of drug combinations, which are considered a gold standard in the first-line approach (Berek et al, 1999;Ozols, 2000), is usually discouraged in the recurrent setting because of higher toxicity, and the lack of any evidence of benefit in terms of survival (Sabbatini et al, 1998;Colombo et al, 1999); nevertheless, the better toxicity profile expressed by some new categories of drugs allows the hypothesis that the rationalised choice of drugs with different mechanisms of action and toxicity patterns might increase the chances of response and favourably affect the clinical outcome. In this context, the combination of two of the above-mentioned drugs, namely GEM and PLD seemed particularly intriguing for several reasons: (i) both the drugs have shown activity in ovarian cancer Gordon et al, 2000Gordon et al, , 2001Markman, 2002); (ii) their different mechanisms of action are likely to hamper a cross resistance; (iii) the combination of GEM and doxorubicin has been reported to result in synergistic antiproliferative activity in vitro (Zoli et al, 1999;Chow et al, 2000); (iv) finally, the nonoverlapping toxicity profiles of GEM and PLD warrant the analysis of their combination in the clinical setting.…”

Synergistic Cytotoxicity and Pharmacogenetics of Gemcitabine and Pemetrexed Combination in Pancreatic Cancer Cell Lines

“…Recent studies have shown the importance of modulating the cell cycle to exploit the effect of drug combinations (8,22). In the present study, flow cytometry demonstrated that both pemetrexed and gemcitabine caused an accumulation of cells in S phase, as a result of the inhibition of DNA synthesis.…”