Synergy of karenitecin and mafosfamide in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines

Abstract

A major barrier to treatment of leptomeningeal disease is the lack of proven combination chemotherapy regimens for intrathecal administration. The purpose of this study was to determine the cytotoxic effects of karenitecin and mafosfamide in vitro against leukemia, medulloblastoma, and neuroblastoma cell lines. A modified methyl tetrazolium (MTT) assay was used to determine the sensitivity of the cells to karenitecin and mafosfamide. Cells were exposed to drug for 72 hr, after which the number of surviving cells was quantitated. For drug combination experiments, cells were exposed to medium alone (controls), single drugs alone (mafosfamide only, karenitecin only) or to different concentrations of the combination of the two drugs (karenitecin + mafosfamide), for a total of 36 concentration pairs per plate. The universal response surface approach (URSA) was used to analyze the cytotoxic effects of the combination of karenitecin and mafosfamide. The IC(50)s of karenitecin and mafosfamide for the various cell lines were similar. For both drugs nearly complete inhibition of cell growth was demonstrated at higher concentrations in all cell lines. In the neuroblastoma cell lines (SK-N-DZ; SK-N-SH) and the DAOY medulloblastoma cell line, the combination of karenitecin and mafosfamide were synergistic. In the D283 medulloblastoma and both the leukemia cell lines (JM1 and Molt-4), the drug interaction was additive. Antagonism was not seen in any cell line. Karenitecin and mafosfamide are additive or synergistic in vitro against tumor types that disseminate to the leptomeninges. These results provide guidance for the choice of potential combination intrathecal regimens.