Aplidine, a Novel Depsipeptide, Shows In Vitro Activity in CLL

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Abstract Number: 2703

Potential Clinical Relevance of Drug Combination Studies with Aplidine

in Experimental Leukemia and Lymphoma Models

Debabrata Banerjee, Medina, Strair, WeiWei Li, Radovan

Vrhovac, Yaroslav Elisseyeff, Jimeno, ph R. Bertino, Cancer

Institute of New Jersey, New Brunswick, NJ; Sloan Kettering Institute

for Cancer Research, New York, NY; Pharmamar, Madrid, Spain.

Aplidine or dehydrodidemnin, is a novel depsipeptide isolated from the

sea tunicate A. Albicans. The phase I clinical program has been

completed with evidence of a positive therapeutic index (TI). The dose

limiting toxicity was found to be muscular, without bone marrow toxicity.

Clinical benefits were noted in different solid tumors and the

compound is now in phase II clinical trials. Experimental studies have

shown that Aplidine can block VEGF secretion in ALL-MOLT4 cells and in

vitro cytotoxic activity at low concentrations (5nM) has been observed

in AML and ALL samples from pediatric patients with de novo or

relapsed ALL and AML. Previous work on the mechanism of action of

Aplidine have suggested that it induces both a G1 and a G2 arrest in

drug treated leukemia cells in vitro.

Besides down regulation of the VEGF receptor, little is known about

the mechanism(s) of action of Aplidine. The apoptotic effects of

Aplidine have been shown to be independent of bax and p53.

In order to determine the cytotoxicity of Aplidine in leukemia and

lymphoma cell lines as well as in primary cells derived from patients,

and to study the possible potentiation of other anticancer agents we

have initiated a systematic study of drug combinations for possible

use in leukemias and lymphomas.

Aplidine was found to be an effective in vitro cytotoxic agent against

primary cells from a patient with preB-ALL (DM4) as well as against

fresh cells obtained from six chronic lymphocytic leukemia patients.

The IC50 value was 10 nM for 3 day exposure with the DM4 line and

after a 11 day exposure with the primary CLL samples.

Drug combination studies were carried out on established cell lines

rather than primary cells. We studied three cell lines viz. K562, CEM

and SKI-DLCL representing acute myeloid leukemia, acute lymphocytic

leukemia and diffuse large cell lymphoma respectively.

The preliminary data shows that Aplidine potentiates the effect of

methotrexate and cytosine arabinoside in K562 and SKI-DLCL lines by

lowering the IC50s for the drugs. Further studies will be designed to

extend these observations which may help in the design of clinical

combination studies and may also be useful in further understanding

the mechanism of action of Aplidine.

Presenter: Debabrata Banerjee

Affiliation: Cancer Institute of New Jersey, New Brunswick, NJ .

Email: banerjed@...

Copyright © 2003 American Association for Cancer Research. All rights

reserved. Published in the Proceedings of the AACR, Volume 44, March 2003.