In vitro toxicity of ET-743 and aplidine, two marine-derived antineoplastics, on human bone marrow haematopoietic progenitors

Albella, Beatriz; Faircloth, Glynn; López-Lázaro, Luis; Guzmán, C.; Jimeno, J.; Bueren, Juan A.

doi:10.1016/s0959-8049(01)00245-3

Cited by 27 publications

(17 citation statements)

References 20 publications

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“…We did not find a decrease in the capacity of stroma pretreated with Aplidin, to support ALL cell viability. Recently (Albella et al, 2002), similar data have been reported on human bone haematopoietic progenitors treated by Aplidin. At concentrations similar to those used in this study Aplidin did not induce growth inhibition in the tested haematopoietic progenitors by using clonogenic assay.…”

Section: Discussionsupporting

confidence: 76%

Effect of Aplidin in acute lymphoblastic leukaemia cells

et al. 2003

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The cytotoxic effect of Aplidin was investigated on fresh leukaemia cells derived from children with B-cell-precursor (BCP) acute lymphoblastic leukaemia (ALL) by using stromal-layer culture system and on four cell lines, ALL-PO, Reh, ALL/MIK and TOM-1, derived from patients with ALL with different molecular genetic abnormalities. In ALL cell lines Aplidin was cytotoxic at nanomolar concentrations. In the ALL cell lines the drug-induced cell death was clearly related to the induction of apoptosis and appeared to be p53-independent. Only in ALL-PO 20 nM Aplidin treatment caused a block of vascular endothelial growth factor (VEGF) secretion and downregulation of VEGF-mRNA, but Aplidin cytotoxicity does not seem to be related to VEGF inhibition since the sensitivity of ALL-PO cells to Aplidin is comparable to that observed for the other cells used. Aplidin induced a G 1 and a G 2 M block in ALL cell lines. In patient-derived leukaemia cells, Aplidin induced a strong cytotoxicity evidenced in a stroma-supported immunocytometric assay. Cells from children with genetic abnormalities such as t(9;22) and t(4;11) translocations, associated with an inferior treatment outcome, were sensitive to Aplidin to the same extent as that observed in other BCP-ALL cases. Aplidin exerted a strong cell killing effect (488%) against primary culture cells from five relapsed ALL cases, at concentrations much lower than those reported to be achieved in plasma of patients receiving Aplidin at recommended doses. Taken together these data suggest that Aplidin could be a new anticancer drug to be investigated in ALL patients resistant to available therapy.

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Section: Discussionsupporting

confidence: 76%

Effect of Aplidin in acute lymphoblastic leukaemia cells

et al. 2003

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“…Aplidine inhibits endothelial cell proliferation, with an IC 50 similar to that observed for tumour cells. Other studies reported that concentrations of aplidine that completely inhibited colony formation by cancer cells were almost ineffective on bone marrow and cord blood haematopoietic progenitor cells, nonstimulated lymphocytes and hepatocytes (Sakai et al, 1996;Gomez et al, 2001;Albella et al, 2002;Erba et al, 2003;Gajate et al, 2003). In agreement, we found that the concentrations of aplidine that affected endothelial cell proliferation had no relevant antiproliferative effect on epithelial cells.…”

Section: Discussionmentioning

confidence: 97%

“…Aplidine was at first selected for its enhanced cytotoxicity against different tumour cells lines and lower myelotoxicity relative to didemnin B (Geldof et al, 1999;Albella et al, 2002). In vitro, aplidine inhibited tumour cell proliferation with an IC 50 in the nanomolar/subnanomolar range, with complete inhibition achieved at 10 nM (Lobo et al, 1997;Erba et al, 2002;Erba et al, 2003).…”

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confidence: 99%

“…Short-term exposure to aplidine rapidly caused apoptosis of tumour cells (Erba et al, 2002;Gajate et al, 2003) and prevented the formation of colonies by explanted tumour cells (Depenbrock et al, 1998). In xenograft models, aplidine showed activity against different tumour types (Albella et al, 2002). Results from early phase clinical trials have confirmed the reduced myelotoxicity of aplidine relative to didemnin B, and have shown activity against certain tumour types such as medullary thyroid carcinoma, renalcell carcinoma, melanoma and tumours of neuroendocrine origin (reviewed in Schwartsmann et al, 2001).…”

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confidence: 99%

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Antiangiogenic activity of aplidine, a new agent of marine origin

et al. 2004

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The antineoplastic compound aplidine, a new marine-derived depsipeptide, has shown preclinical activity in vitro on haematological and solid tumour cell lines. It is currently in early phase clinical trials. The exact mechanism of action of this anticancer agent still needs to be clarified. We have previously reported that aplidine blocks the secretion of the angiogenic factor vascular endothelial growth factor (VEGF) by the human leukaemia cells MOLT-4, suggesting a possible effect on tumour angiogenesis. This study was designed to investigate the antiangiogenic effect of aplidine. In vivo, in the chick embryo allantoic membrane (CAM) assay, aplidine inhibited spontaneous angiogenesis, angiogenesis elicited by exogenous VEGF and FGF-2, and induced by VEGF overexpressing 1A9 ovarian carcinoma cells. In vitro, at concentrations achievable in the plasma of patients, aplidine inhibited endothelial cell functions related to angiogenesis. It affected VEGF-and FGF-2-induced endothelial cell proliferation, inhibited cell migration and invasiveness assessed in the Boyden chamber and blocked the production of matrix metalloproteinases (MMP-2 and MMP-9) by endothelial cells. Finally, aplidine prevented the formation of capillary-like structures by endothelial cells on Matrigel. These findings indicate that aplidine has antiangiogenic activity in vivo and inhibits endothelial cell functional responses to angiogenic stimuli in vitro. This effect might contribute to the antineoplastic activity of aplidine.

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“…These in vitro concentrations correlate with the drug levels reached in patients treated with pharmacologically appropriate doses of Aplidin. 27 Since in phase I and II clinical studies with aplidin patients have been pretreated with L-carnitine to prevent myotoxicity, we tested the influence of L-carnitine preincubation on aplidin cytotoxicity in vitro. L-carnitine in two different concentrations did not influence the cytotoxicity of aplidin in vitro towards leukemic cells, as expressed by the LC50 and LC75 values in the MTT assay.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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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.

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In vitro toxicity of ET-743 and aplidine, two marine-derived antineoplastics, on human bone marrow haematopoietic progenitors

Cited by 27 publications

References 20 publications

Effect of Aplidin in acute lymphoblastic leukaemia cells

Effect of Aplidin in acute lymphoblastic leukaemia cells

Antiangiogenic activity of aplidine, a new agent of marine origin

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

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