Cytotoxicity and neurocytotoxicity of new marine anticancer agents evaluated using in vitro assays.
OBJECTIVE
New classes of anticancer drugs, isolated from marine organisms, have been shown to possess cytotoxic activity against multiple tumor types. Aplidine, didemnin B, and isohomohalichondrin B (IHB), among the more promising antitumor candidates, have been evaluated in the present study on a comparative basis in terms of their antiproliferative activity and neurotoxic effects in vitro.


METHODS
Using a panel of different human, prostatic cancer cell lines (DU 145, PC-3 and LNCaP-FGC) the effects of Aplidine, didemnin B, and IHB on tumor cell proliferation were tested in a colorimetric (XTT) assay and compared with the effects of vincristine, vinorelbine, and Taxol. Under analogous in vitro conditions these drugs were also monitored for neurocytotoxic effects using a PC 12 cell line based model.


RESULTS
Didemnin B and - especially - Aplidine were more effective in the inhibition of prostate 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 neurotoxicity assays. IHB was found to exert even more potent antiproliferative 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 drug withdrawal, the neurotoxic damage, inflicted by aplidine or IHB appeared to be more long lasting than after vincristine or vinorelbine exposure.


CONCLUSIONS
These results point to high antiproliferative activity of aplidine and IHB in prostate cancer. At the same time, the data urge some caution in the clinical use of these agents because of potential neurotoxic side-effects. The use of a newly formulated Aplidine may involve a more favorable therapeutic profile.
Geldof
A A
AA
Department of Urology/Nuclear Medicine, University Hospital, Vrije Universiteit, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. aa.geldof@azvu.nl
Mastbergen
S C
SC
Henrar
R E
RE
Faircloth
G T
GT
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D047630:Depsipeptides; D004354:Drug Screening Assays, Antitumor; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced; D009842:Oligopeptides / Q000494:pharmacology* / Q000633:toxicity; D016716:PC12 Cells; D017239:Paclitaxel / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000633:toxicity; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011714:Pyrans / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D013141:Spiro Compounds / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D000077235:Vinorelbine
D000970:Antineoplastic Agents; D047630:Depsipeptides; D006131:Growth Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011714:Pyrans; D013141:Spiro Compounds; C099151:isohomohalichondrin B; C030051:didemnins; D014750:Vincristine; D014747:Vinblastine; D017239:Paclitaxel; D000077235:Vinorelbine; C098980:plitidepsin