Synergistic interaction between paclitaxel and 8-chloro-adenosine 3 ',5 '-monophosphate in human ovarian carcinoma cell lines

Taxol is a unique anticancer agent that is used in treatment of advanced ov arian cancer. Taxol exposure results in the polymerization and stabilizatio n of the microtubule skeleton of eukaryotic cells, hence blocking replicati on and intracellular motility, 8-Chloro-adenosine 3',5'-monophosphate (d-Cl -cAMP) is a cAMP analogue, currently in Phase II clinical trials, that disp lays growth inhibition at micromolar concentrations. The aim of this study was to assess the nature of the interaction between 8-Cl-cAMP and paclitaxe l using the combination index (CI) method of Chou and Talalay, which uses t he median-effect analysis, Two ovarian cancer cell lines, A2780 and OAW42, which differ in sensitivity to both drugs, were tested using the fixed-rati o design using various scheduling regimens. Concurrent exposure of both dru gs resulted in highly synergistic interactions in both cell lines. CIs (mea n +/- SE) with this schedule were 0.182 +/- 0.016, 0.315 +/= 0.32, and 0.61 8 +/- 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 88% cell kill, respectively, in OAW42 cells, In both cell lines, synergy was ef fective over a 4-fold log range of concentration for either drug, Sequencin g with paclitaxel for 24 h prior to 8-Cl-cAMP was the most effective regime n; 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 e ffective regimen. In conclusion, the combination of paclitaxel and 8-Cl-cAM P is highly synergistic in ovarian carcinoma cell lines, suggesting that d- Cl-cAMP may stimulate the antitumor effect of the taxanes.