Antitumor activity of didemnin B in the human tumor stem cell assay.
In vitro studies of the schedule dependency and cytotoxicity of didemnin B, a novel depsipeptide isolated from a Carribean tunicate (Didemnidae), were carried out in fresh tumor cells obtained from biopsies from 39 cancer patients using the human tumor stem cell assay. Two schedules of drug exposure were examined (1 h and continuous exposure in the agar). Tumor cells from nine of 26 patients (34.6%) showed reduced survival of tumor-colony forming units to 30% of control or less at the 0.01 microgram level in the continuous exposure studies. Cells from eight of 17 patients (47%) showed a similar degree of sensitivity to didemnin after a 1-h exposure to 0.1 microgram prior to plating. The median ID50 values were 4.2 X 10(-3) micrograms/ml and 46 X 10(-3) micrograms/ml for continuous and 1-h exposures, respectively. A clear dose-response relationship was observed with both dosage schedules. Comparison of the slopes of the continuous and 1-h exposures and of the ID50 of the drug schedules suggests that didemnin is a cell-cycle-non-specific cytotoxic agent. Significant in vitro antitumor activity was observed at low concentrations against carcinomas of the breast, ovary, and kidney, and also mesothelioma and sarcoma. These results can provide pharmacologic goals to be achieved in phase I clinical trial. Further in vitro testing should help select tumor types for study in phase II trials of this very promising new anticancer drug.
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D009369:Neoplasms / Q000473:pathology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D010456:Peptides, Cyclic; C030051:didemnins