Cytotoxicity and neurocytotoxicity of new marine anticancer agents evaluated using in vitro assays

Purpose: New classes of anticancer drugs, isolated from marine organisms, h ave been shown to possess cytotoxic activity against multiple tumor types. Aplidine, didemnin B, and isohomohalichondrin B (IHB), among the more promi sing antitumor candidates, have been evaluated in the present study on a co mparative basis in terms of their antiproliferative activity and neurotoxic effects in vitro. Methods: Using a panel of different human, prostatic can cer cell lines (DU 145, PC-3 and LNCaP-FGC) the effects of Aplidine, didemn in B, and IHB on tumor cell proliferation were tested in a colorimetric (XT T) assay and compared with the effects of vincristine, vinorelbine, and Tax ol. Under analogous in vitro conditions these drugs were also monitored for neurocytotoxic effects using a PC 12 cell line based model. Results: Didem nin B and - especially Aplidine were more effective in the inhibition of pr ostate cancer cell proliferation than vincristine, vinorelbine or Taxol at concentration levels between 5 and 50 pmol/ml. At these same concentrations , however, Didemnin B and Aplidine were also most potent in the in vitro ne urotoxicity assays. IHB was found to exert even more potent antiproliferati ve activity (at concentration levels between 0.05 and 0.1 pmol/ml). However , neurotoxic effects were also found to be present at these levels. After d rug withdrawal, the neurotoxic damage, inflicted by aplidine or IHB appeare d to be more long lasting than after vincristine or vinorelbine exposure. C onclusions: These results point to high antiproliferative activity of aplid ine and IHB in prostate cancer. At the same time, the data urge some cautio n in the clinical use of these agents because of potential neurotoxic side- effects. The use of a newly formulated Aplidine may involve a more favorabl e therapeutic profile.