dolastatin-10 and Prostatic-Neoplasms

Dolastatin-10 is a natural, cytotoxic peptide with microtubule-inhibitory and apoptotic effects. It has demonstrated in vitro and in vivo efficacy in the DU-145 human prostate cancer model. A Phase II clinical trial was designed in patients with hormone-refractory prostate cancer. Dolastatin-10 was administered at a dose of 400 microg/m2 i.v. every 3 weeks. Dose escalation to 450 microg/m2 was permitted. Toxicity evaluation was conducted every 2 weeks, and assessment of response was done at the end of every two cycles. Sixteen patients were enrolled between October 1998 to December 1999. The median age was 71 years (range, 59-79 years). Median prostate-specific antigen value was 108 ng/ml (range, 15.3-1672 ng/ml). Of the 15 eligible patients, 7 were Caucasian and 8 were African-American. Eight patients had bone-only metastases, and seven had measurable disease with or without bone metastases. A total of 56 cycles have been administered. Only 2 patients required dose adjustment because of toxicity, and in 5 patients, dose escalation was feasible to 450 microg/m2. The major toxicities observed were grade 3 and 4 neutropenia in 8 patients and grade 3 neuropathy in 1 patient. All 15 patients are evaluable for response. Three patients demonstrated stable disease; 2 of these had bone disease, and 1 had nodal metastasis. All others had disease progression. Dolastatin-10 is very well tolerated in this elderly, pretreated population but lacks significant clinical activity as a single agent.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Depsipeptides; Humans; Male; Middle Aged; Neoplasm Metastasis; Oligopeptides; Prostatic Neoplasms

Dolastatin 10 is an anticancer peptide isolated from the sea hare, Dolabela auricularia, which is currently in phase I trials.. 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.. 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.. 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.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Cell Division; Depsipeptides; Drug Screening Assays, Antitumor; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Mollusca; Oligopeptides; Prostatic Neoplasms; Tubulin; Tumor Cells, Cultured