In vitro evaluation of potentially effective gemcitabine combination therapy for exocrine pancreatic carcinoma

: The aim of the present study was to define potentially synergistic gemcitabine drug combinations for the treatment of pancreatic adenocarcinoma by using a tumour-specific in vitro screening system. The anticancer drug screening system used for these experiments consisted of four different established human pancreatic adenocarcinoma cell lines (BxPc-3, Panc-1, ASPC-1, Ca-pan-1) and the Microculture Tetrazolium (MTT) Assay for quantification of cytotoxic drug effects. To define single agent activities, dose-response curves, IC 50 values, and in order to validate the test system, in a first step gemcitabine and several conventional anticancer drugs including 5-FU, cisplatin, epirubicin, and mitomycin C were tested at 10 different concentrations ranging from 0.001 to 100 micrograms/ml. The effectiveness of various gemcitabine combinations was subsequently determined by using clinically relevant in vitro drug concentrations, and was rated as synergistic, additive or subadditive according to the criteria of Aapro. Overall, a heterogeneous chemosensitivity pattern was noted within the four tested cell lines. In agreement with the known chemotherapeutic refractoriness of pancreatic cancer, major cytotoxic effects were only seen with use of rather high drug concentrations. Investigation of various drug exposure times revealed a superior antiproliferative activity of gemcitabine and the other compounds in case of prolonged incubation. During subsequent drug combination experiments, gemcitabine + cisplatin and gemcitabine + epirubicin resulted in synergistic activity in 2/4 cell lines each. As opposed to the poor activity of single agents, a > 50% growth inhibition (in vitro response) was noted in 3 and 2 cell lines, respectively. Experimental data obtained with this pancreatic cancer specific in vitro screening system suggest that dose escalation or prolonged administration of gemcitabine, as well as the combination of this drug with cisplatin or epirubicin might result in improved therapeutic results. Encouraging preliminary results obtained in phase II studies seem to support the potential clinical relevance of the described disease-oriented screening system.