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Annals of Oncology Advance Access originally published online on July 13, 2005
Annals of Oncology 2005 16(10):1667-1674; doi:10.1093/annonc/mdi311
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© 2005 European Society for Medical Oncology

VEGF inhibition and cytotoxic effect of aplidin in leukemia cell lines and cells from acute myeloid leukemia

M. Biscardi1, R. Caporale1, F. Balestri1, S. Gavazzi1, J. Jimeno2 and A. Grossi1,*

1 U.O. Hematology, Azienda Ospedaliera Careggi, University of Florence, Florence, Italy; 2 PharmaMar SAU, Research and Development, Comenar Viejo, Madrid, Spain

* Correspondence to: Dr A. Grossi, Istituto Leonardo da Vinci, Hematology, Via Colletta 22/r, 50100 Firenze, Italy. Tel: +39-338-5200467; Fax: +39-055-2487230; E-mail: alberto_grossi{at}libero.it

Background: Aplidine (APL) is a marine depsipeptide isolated from the Mediterranean tunicate Aplidium albicans that is under clinical phase II development. In contrast to the lack of bone marrow toxicity reported in phase I/II studies, it has been shown to induce cytotoxicity at very low concentration against lymphoblastic leukemia blast, as well as having an impact in the vascular endothelial growth factor (VEGF)/VEGF receptor 1 loop.

Patients and methods: To confirm these findings we investigated APL-related VEGF inhibition and its cytotoxic effect on myeloid leukemic cells lines (K-562, HEL and HL60) and fresh leukemia blasts derived from 30 patients with acute myeloid leukemia (AML). The conventional active 4-demetoxi-daunorubicin (idarubicin; IDA) was included as a positive control.

Results: APL was found to be significantly (P < 0.001) more active than IDA in obtaining 50% growth-inhibition in K-562, HEL and HL60 cell lines. Results obtained with AML blast cells were superimposible. ID50 ranged from 0.024 to 0.610 µM for IDA (0.200 ± 0.176) and from 0.001 to 0.108 µM for APL (0.020 ± 0.031). Annexin V tests and cell cycle analysis performed on cell lines confirmed the stronger citotoxic capability of APL as apoptotic inducer and as a G1 blocker. The inhibitory effects of APL on VEGF release and secretion have been confirmed by ELISA tests performed on HEL: the VEGF concentration in cell surnatant was reduced from 169 to 36 pg/ml after 24 h of exposure to a pharmacological concentration of APL.

Conclusions: APL harbors a strong in vitro antileukemic activity at a concentration achievable in patients at non-myelotoxic doses. Our data also support the notion of an impact on VEGF secretion. Clinical studies with this new marine-derived compound in relapsed/resistant leukemia are underway.

Key words: aplidine, marine compounds, myeloid leukemia, VEGF inhibiton


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