Sequence dependent synergistic cytotoxicity between etoposide and fluoropyrimidines

The cytotoxic interactions between etoposide and two fluoropyrimidines (FP), 5-fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd), were determined in L1210 cells by soft agar clonogenic assay and in five human adenocarcinoma cell lines by colony growth assay. The administration of etoposide prior to FP resulted in synergistic cytotoxicity in L1210, HCT-8, Mia PaCa, MCF-7, and T47-D cells while the reverse sequence resulted in additive or antagonistic cytotoxicity in L1210, HCT-8, and Mia PaCa cells. Etoposide prior to FdUrd produced more DNA single strand breaks than expected in L1210 cells, while the reverse sequence produced fewer than expected. The sequence--dependent synergistic cytotoxicity of etoposide--FP correlates with relative DNA single strand break production in L1210 cells.