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

doi:doi:10.1038/sj.leu.2402972

Leukemia (2003) 17, 1338–1343. doi:10.1038/sj.leu.2402972

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

D Bresters^1,2, A J F Broekhuizen¹, P Kaaijk¹, G T Faircloth³, J Jimeno⁴ and G J L Kaspers¹

¹Department of Pediatric Hematology/Oncology, VU University Medical Center, Amsterdam, the Netherlands
²Department of Pediatric Immunology, Hematology, Oncology, Bone Marrow Transplantation and Auto-immune Diseases, Leiden University Medical Center, Leiden, the Netherlands
³PharmaMar SA, Research and Development, Tres Cantos (Madrid), Spain
⁴PharmaMar USA, Inc., Cambridge, MA, USA

Correspondence: Dr GJL Kaspers, Department of Pediatric Hematology/Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Fax: +31 20 4442 422

Received 26 November 2002; Accepted 7 March 2003.

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Abstract

To determine the potential of aplidin as a cytotoxic agent in pediatric leukemia, we tested bone marrow (BM) 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. Aplidin 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 aplidin, had no effect on aplidin 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 (=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 aplidin. In conclusion, we show that aplidin has selective cytotoxicity in vitro towards childhood leukemia cells and generally lacks crossresistance with other known cytotoxic drugs, which warrants clinical studies.