Influence of the schedule of exposure on the cytotoxic effect of melphalan on human 8226 and A2780 cells

Melphalan was investigated for antitumoral activity using two schedules of exposure (solid versus sequential exposure) in two human cancer cell lines (8226 and A2780). Sequential exposure of melphalan was more effective than solid exposure at the same total dose. The IC50 values averaged 8.2 (solid exposure) and 0.16μg/ml (sequential exposure) for 8226 cells (myeloma), and 7.5 (solid) and 0.53μg/ml (sequential) for A2780 cells (ovarian carcinoma). Intracellular melphalan accumulation, determined by high-performance liquid chromatography, showed that the area under the intracellular concentration of melphalan versus time curve (between 0 and 30h) was significantly higher after sequential doses (9.4μg/ml×h) than after solid dose (6.6μg/ml×h). Moreover, intracellular/extracellular concentration ratios indicated that melphalan uptake followed a passive transport system. The increase of both duration of exposure (11h after solid exposure versus 20h after sequential doses) and intracellular concentrations 5–6h after the beginning of the experiment (approximately 3 times higher after sequential doses) indicate sequential administration of melphalan could be more effective than solid exposure.