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Synergistic Interaction between Paclitaxel and 8-Chloro-adenosine 3',5'-Monophosphate in Human Ovarian Carcinoma Cell Lines¹

Department of Oncology, Queens University of Belfast, Belfast City Hospital, Belfast, Northern Ireland, United Kingdom BT9 7AB

Taxol is a unique anticancer agent that is used in treatment of advanced ovarian cancer. Taxol exposure results in the polymerization and stabilization of the microtubule skeleton of eukaryotic cells, hence blocking replication and intracellular motility. 8-Chloro-adenosine 3',5'-monophosphate (8-Cl-cAMP) is a cAMP analogue, currently in Phase II clinical trials, that displays growth inhibition at micromolar concentrations. The aim of this study was to assess the nature of the interaction between 8-Cl-cAMP and paclitaxel using the combination index (CI) method of Chou and Talalay, which uses the median-effect analysis. Two ovarian cancer cell lines, A2780 and OAW42, which differ in sensitivity to both drugs, were tested using the fixed-ratio design using various scheduling regimens. Concurrent exposure of both drugs resulted in highly synergistic interactions in both cell lines. CIs (mean ± SE) with this schedule were 0.182 ± 0.016, 0.315 ± 0.32, and 0.618 ± 0.637 at 20, 50, and 80% cell kill, respectively, in A2780 cells and 0.001 ± 0.0009, 0.016 ± 0.0075, and 0.184 ± 0.168 at 20, 50, and 80% cell kill, respectively, in OAW42 cells. In both cell lines, synergy was effective over a 4-fold log range of concentration for either drug. Sequencing with paclitaxel for 24 h prior to 8-Cl-cAMP was the most effective regimen; it resulted in consistently low CIs of up to the 90% cell kill level for both cell lines. Exposure to 8-Cl-cAMP prior to paclitaxel was the least effective regimen. In conclusion, the combination of paclitaxel and 8-Cl-cAMP is highly synergistic in ovarian carcinoma cell lines, suggesting that 8-Cl-cAMP may stimulate the antitumor effect of the taxanes.

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