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

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 ¼ 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 ¼ 19) and PB (n ¼ 13) cells were more resistant to aplidin than leukemic cells (median two-to seven-fold, P ¼ 0.001 and median four-to 11-fold, Po0.0001, respectively). In leukemia samples, no significant crossresistance between aplidin and other cytotoxic drugs was found, except for a trend for correlation with 2 0 ,2 0 -difluorodeoxycytidine (q ¼ 0.71, P ¼ 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.

Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin™

“…Results from phase I clinical trials showed signs of clinical benefit, in terms of stabilisation of the disease, and a favourable tolerability profile, with mild and relatively infrequent side effects (Anthoney et al , 2000; Armand et al , 2001; Bowman et al , 2001; Mauroun et al , 2001; Ciruelos et al , 2002). In addition, based on recent results showing that APL presents selective cytotoxicity in vitro against childhood leukaemia cells, a phase I clinical trial to study the effect of APL in pediatric leukaemia is under implementation (Bresters et al , 2003; Erba et al , 2003). Aplidin™ is currently in phase II clinical trials for renal, head and neck, pancreas, lung (NSCLC) and colorectal cancers, and medullary thyroid carcinoma.…”

Levels of p27kip1 determine Aplidin sensitivity

“…Results from phase I clinical trials showed signs of clinical benefit, in terms of stabilization of the disease, and a favorable tolerability profile, with mild and relatively infrequent side effects (4 -8). Aplidin has selective cytotoxicity in vitro toward childhood leukemia cells and generally lacks cross-resistance with other known cytotoxic drugs (9,10). Aplidin is currently in phase II clinical trials in a variety of solid tumors and hematologic malignancies.…”

Antitumour and antiangiogenic effects of Aplidin® in the 5TMM syngeneic models of multiple myeloma

“…Aplidin is an extremely potent inducer of apoptosis, with concentrations that caused 50% inhibition of tumour growth (IC 50 ) in vitro in a low nanomolar range, and it also exhibits strong antitumor activity in xenograft models (Urdiales et al, 1996;Erba et al, 2002;Broggini et al, 2003;Biscardi et al, 2005). In different haematological malignancies, such as acute lymphoblastic leukaemia, acute myeloid leukaemia and lymphoma, the drug is cytotoxic on primary human cells and cell lines, even on leukaemic cells carrying cytogenetic abnormalities that have poor prognostic implications (Bresters et al, 2003;Erba et al, 2003;Gajate et al, 2003). In addition to the cytotoxic properties of Aplidin, the molecule exhibits also strong antiangiogenic activity.…”