Effect of Aplidin in acute lymphoblastic leukaemia cells

Abstract

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.

Antiangiogenic activity of aplidine, a new agent of marine origin

“…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.…”

“…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). 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).…”

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.…”

Organismos marinhos como fonte de novos fármacos: histórico & perspectivas

“…Sabe-se que seus efeitos implicam principalmente no bloqueio da divisão celular (devido à inibição da síntese de DNA e proteínas) e no enfraquecimento da angiogênese tumoral (pela diminuição da secreção de VEGF e da expressão do receptor VEGF-r1 e à inibição da enzima ornitinadescarboxilase). [99][100][101] A aplidina foi licenciada para a PharmaMar sob o registro de Aplidin ® (plitidepsina) e ingressou nos testes clínicos em 1999, vindo a se beneficiar diretamente das informações geradas nos estudos com didemnina B. Interessantemente, a simples oxidação do radical 2-hidroxipropanoil a 2-oxopropanoil transforma substancialmente o seu perfil toxicológico. 10,30 De modo geral, o tratamento com aplidina tem sido bem tolerado e a toxicidade neuromuscular, seu principal fator limitante, pode ser contornada com a coadministração de L-carnitina.…”