Studies of synergistic and antagonistic combinations of conventional cytotoxic agents with the multiple eicosanoid pathway modulator LY 293111.
키워드
요약
The arachidonic acid metabolic pathway is currently under active investigation as a promoter of malignancy and several molecules have been synthesized to block either the cyclooxygenase or lipoxygenase branches. LY 293111 is an oral agent known to be a leukotriene B4 antagonist, a 5-lipoxygenase inhibitor and a peroxisome proliferator-activated receptor (PPAR)-gamma agonist with cytotoxic properties in cell lines. We have studied this agent with classical chemotherapeutic agents in a 72-h culture with cell lines using median-effect analysis as a measure of antagonism or synergy. LY 293111 displays global synergy with the active metabolite of irinotecan, SN-38, in the majority of cell lines, synergistic to additive effects with gemcitabine in bladder cancer cell lines, and synergism with 5'-DFUR (the active metabolite of capecitabine) in two breast cancer and one sarcoma cell line. These effects occur at clinically attainable concentrations. The addition of a proteosome inhibitor to the LY 293111 and SN-38 combination markedly enhanced the cytotoxic effects in the sarcoma cell line. As the toxicity of LY 293111 in man is not hematological, this agent may have a role in combination therapy of selected malignancies.