Taxol in combination with doxorubicin or etoposide possible antagonism in vitro

Abstract

Background. Taxol is a novel chemotherapeutic agent that promotes microtubule assembly and stabilizes tubulin polymer formation. Clinical evaluation of its antineoplastic activity as a single agent and in combination with other chemotherapeutic drugs is in progress. Methods. To evaluate the effect of combining taxol with other commonly used antineoplastic agents, clonogenic survival of human breast cancer MCF7 cells, human lung adenocarcinoma A549 cells, and human ovarian cancer OVG1 cells were assayed after an initial exposure to taxol for 24 hours (approximately LD90 for taxol), followed by a 1‐hour incubation with varying concentrations of doxorubicin or etoposide (total taxol incubation time, 25 hours). Results. When corrected for taxol‐induced cytotoxicity, doxorubicin and etoposide caused less cell killing in the presence of taxol compared with control incubations of doxorubicin and etoposide alone. To determine if a different schedule of drug application resulted in a similar finding, MCF7, A549, and OVG1 cells were exposed to doxorubicin for 1 hour, followed by incubation with varying concentrations of taxol for 24 hours. Less‐than‐additive cytotoxicity for the combination of taxol and doxorubicin was found. Flow cytometry studies in MCF7 cells showed that taxol caused a G2/M cell cycle block. Fewer cells were found to be in S‐phase, which is the most doxorubicin‐sensitive phase of the cell cycle. The application of doxorubicin or etoposide to MCF7 cells for 1 hour resulted in partial G1 and G2/M cell cycle blocks. Fewer cells were found to be moving through the cell cycle, which is likely required for taxol cytotoxicity. Conclusion. Although direct antagonism of the cytotoxicity of doxorubicin or etoposide by taxol has not been proven, there is less‐than‐additive in vitro cytotoxicity when taxol is combined with these chemotherapeutic agents. The clinical implications of these findings are unknown; however, these findings generate concern about the combination of these agents in clinical trials and suggest that additional studies to determine optimal scheduling are needed.

Is Cell Death a Critical End Point for Anticancer Therapies or Is Cytostasis Sufficient?

“…This observation fits the paradigm of flavopiridol as a static agent and the well-established observation that cytotoxicity of a taxane is very vulnerable to anything that arrests cycling cells, if the arrest occurs before the taxane is added. For example, administering the cytostatic agent doxorubicin leads to a p21-mediated G 1 arrest and impaired taxane cytotoxicity (49). Allowing for differences in cellular context, similar results have been observed with the p21-mediated G 1 arrest induced by the histone deacetylase inhibitors (50,51).…”

Greater antitumor efficacy of paclitaxel administered before epirubicin in a mouse mammary carcinoma

“…Despite clinical interest, the in vitro experiments are not very encouraging (Hahn et al 1993;Bajorko et al 1994) and have produced contradictory results: a less-thanadditive cytotoxicity in human breast cancer MCF7 cells, human lung adenocarcinoma A549 cells and human ovarian cancer OVG1 cells (Hahn et al 1993), an antagonistic eect (in 4/10 cases) and a synergistic eect (in 1/10 cases) in some mammary carcinoma primary cell lines (Bajorko et al 1994). In vitro results can give important indications, although they may not be exactly transferable to in vivo situations.…”

“…The possibility of combining paclitaxel and anthracycline has been evaluated in vitro with contradictory results (Hahn et al 1993;Bajorko et al 1994;Decorti et al 1996) ranging from antagonistic to synergic eects in dierent cell lines, sometimes depending on the schedules used. Clinical investigations have highlighted the considerable interest in this combination despite the involvement of taxanes and anthracyclines in multidrug resistance (Podda et al 1992).…”

Docetaxel and gemcitabine activity in NSCLC cell lines and in primary cultures from human lung cancer

“…Moreover, recent studies have shown the importance of recognizing specific perturbations induced by the different drugs on cell cycle when designing combination or sequential therapies in order to increase additive or synergistic effects and avoid antagonistic effects (Hahn et al, 1993;Theodossiou et al, 1998;Zoli et al, 1999).…”