In vitro cytotoxicity of aplidin and crossresistance with other cytotoxic drugs in childhood leukemic and normal bone marrow and blood samples: A rational basis for clinical development

To determine the potential of aplidin as a cytotoxic agent in pediatric leukemia, we tested bone marrow (13M) and peripheral blood (PB) samples (n = 72) of children with different types of leukemia and healthy children in the methyl-thiazol-tetrazolium assay. Also, we compared these results with other cytotoxic drugs. Apildin was cytotoxic in vitro at nanomolar concentrations, in a dose-dependent fashion. L-carnitine, that is applied in clinical studies to prevent myotoxicity caused by apildin, had no effect on apildin cytotoxicity in vitro. Aplidin cytotoxicity in vitro was not different when initial and relapsed acute lymphoblastic leukemia (ALL) or initial ALL and initial acute myeloid leukemia were compared. However, normal BM (n = 19) and PB (n = 13) cells were more resistant to aplidin than leukemic cells (median two-to seven-fold, P=0.001 and median four-to 11-fold, P<0.0001, respectively). In leukemia samples, no significant crossresistance between aplidin and other cytotoxic drugs was found, except for a trend for correlation with 2′,2′-difluorodeoxycytidine (p = 0.71, P = 0.02). In normal BM samples, significant crossresistance with the epipodophyllotoxins was found, which is not readily explained by the currently known mechanisms of action of apildin. In conclusion, we show that aplidin has selective cytotoxicity in vitro towards childhood leukemia cells and generally lacks cross-resistance with other known cytotoxic drugs, which warrants clinical studies.