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
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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