This project has continued to focus upon the potential mechanism(s) underlying the selective brain tumor (CNS) cell line cytotoxicity of certain quaternized ellipticine derivatives. Sensitivity of these glial derived human brain tumor cells to N2-methyl-9-methoxyellipticinium acetate (MMEA) correlates with peak cellular concentration of the drug (r=0.976, p<0.0001). Peak cellular concentration of MMEA by sensitive CNS cell lines is achieved 10-15 hours following initiation of drug exposure and represents intracellular drug concentrations several hundred-fold in excess of that found in the extracellular medium. Cellular accumulation is mediated by a high-affinity, sodium-independent transport system which is competitively inhibited by the plant alkaloid reserpine, secondary and tertiary tricyclic antidepressant drugs and, with much lower affinity by catecholamine neuro-transmitters and serotonin.
