BACKGROUND: Dolastatin 10 is an anticancer peptide isolated from the sea hare, Dolabela auricularia, which is currently in phase I trials. METHODS: The effects of dolastatin 10 on the DU-145 human prostate cancer cell line were studied both in tissue culture and in athymic nude mice. In tissue culture, after dolastatin 10 treatment, cell cycle kinetics were measured using propidum iodide, apoptosis was estimated using the TUNEL assay, and tubulin architecture studied by direct immunofluorescence. RESULTS: At concentrations of 1 nM (IC50 = 0.5 nM), dolastatin 10 completely inhibited the growth in tissue culture of human prostate cancer DU-145 cells. Growth inhibition was correlated with the arrest of these cells in G2/M and alpha-tubulin depolymerization. In athymic mice at a dose of 5 micrograms every 4 days i.p., dolastatin 10 blocked the diaphragmatic invasion of DU-145 tumor cells. CONCLUSIONS: Dolastatin 10 is a novel marine-derived compound with activity in the treatment of human prostate cancer in animals. The mechanism of action of this agent involves tubulin depolymerization but not the induction of apoptosis.
BACKGROUND:Dolastatin 10 is an anticancer peptide isolated from the sea hare, Dolabela auricularia, which is currently in phase I trials. METHODS: The effects of dolastatin 10 on the DU-145 humanprostate cancer cell line were studied both in tissue culture and in athymic nude mice. In tissue culture, after dolastatin 10 treatment, cell cycle kinetics were measured using propidum iodide, apoptosis was estimated using the TUNEL assay, and tubulin architecture studied by direct immunofluorescence. RESULTS: At concentrations of 1 nM (IC50 = 0.5 nM), dolastatin 10 completely inhibited the growth in tissue culture of humanprostate cancer DU-145 cells. Growth inhibition was correlated with the arrest of these cells in G2/M and alpha-tubulin depolymerization. In athymic mice at a dose of 5 micrograms every 4 days i.p., dolastatin 10 blocked the diaphragmatic invasion of DU-145 tumor cells. CONCLUSIONS:Dolastatin 10 is a novel marine-derived compound with activity in the treatment of humanprostate cancer in animals. The mechanism of action of this agent involves tubulin depolymerization but not the induction of apoptosis.
Authors: Hedy L Kindler; Peter K Tothy; Robert Wolff; Richard A McCormack; James L Abbruzzese; Sridhar Mani; Kurombi T Wade-Oliver; Everett E Vokes Journal: Invest New Drugs Date: 2005-10 Impact factor: 3.850