Phase II trial of didemnin-B in advanced epithelial ovarian cancer

Cain, Joanna M.; Liu, P. Y.; Ds, Alberts; Gallion, Holly H.; Laufman, Leslie Rodgers; O’Sullivan, Janet; Weiss, Geoffrey R.; Bickers, John N.

doi:10.1007/bf01275473

Cited by 17 publications

(12 citation statements)

References 4 publications

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“…Liver residues of [ 3 H]didemnin B in mice of Study 2 at 6-12 h were in the range that damaged cancer cells in vitro [28,29]. High concentrations in the liver may help to explain the acute hepatotoxicity noted in cancer patients as well as in rats and dogs in toxicity studies [3,4,24,30,31].…”

Section: Discussionmentioning

confidence: 96%

Fate of tritiated didemnin B in mice: excretion and tissue concentrations after an intraperitoneal dose

Beasley

Bruno

Burner

et al. 2005

Biopharm. Drug Dispos.

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Didemnin B has undergone trials in cancer patients, and has antiviral and immunosuppressive properties. [(3)H]didemnin B was administered intraperitoneally (i.p.) to mice at 320 or 1280 microg/kg. Urine and feces were collected until 168 h, at which time the mice were killed and tissues collected. Additionally, [(3)H]didemnin B was given i.p. at 320 microg/kg, and mice were killed at 1-120 h post-dosing. Radiolabel increased rapidly in blood then rapidly declined. Most radiolabel in urine, feces and tissues represented parent compound. Concentrations of [(3)H]didemnin B were greatest in the liver > gallbladder > lower digestive tract congruent with pancreas > spleen > kidney congruent with adipose tissue congruent with urinary bladder with urine. The pancreas had the longest terminal half-life of the tissues and the highest radioactivity at 7 days. Intermediate concentrations were in the duodenum congruent with jejunum > lung > iliopsoas > stomach congruent with testes congruent with skin > heart. Low concentrations were in the humerus congruent with femur congruent with quadriceps congruent with triceps >> brain. Fecal excretion accounted for 45.9%-58.3% of the dose and declined after 24 h, followed by an increase, suggesting possible enterohepatic recycling or an impact of circadian rhythms. Urinary excretion accounted for 18.4%-25.2% of the dose, but was minimal after 24 h. The concentrations were highest in organs previously found to be sensitive in animals and humans. Didemnin B should be evaluated in animal models for treatment of pancreatic cancer.

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Section: Discussionmentioning

confidence: 96%

Fate of tritiated didemnin B in mice: excretion and tissue concentrations after an intraperitoneal dose

Beasley

Bruno

Burner

et al. 2005

Biopharm. Drug Dispos.

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“…Using this unbiased approach we unexpectedly discovered that CGs are potent general protein synthesis inhibitors in a variety of normal and transformed human cells. Whereas drugs such as sirolimus (rapamycin) that inhibit the translation of a specific subset of mRNAs are now used to treat certain neoplasms, the general protein synthesis inhibitors have proven to be very toxic and not useful in the treatment of cancer [25], [26], [27], [28], [29], [30]. Therefore, our findings have direct implications for the validity of CGs as promising cancer drugs and discourage further clinical testing of cardiac glycosides or their derivatives as anti-cancer agents.…”

Section: Introductionmentioning

confidence: 99%

Cardiac Glycosides Induce Cell Death in Human Cells by Inhibiting General Protein Synthesis

et al. 2009

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BackgroundCardiac glycosides are Na+/K+-pump inhibitors widely used to treat heart failure. They are also highly cytotoxic, and studies have suggested specific anti-tumor activity leading to current clinical trials in cancer patients. However, a definitive demonstration of this putative anti-cancer activity and the underlying molecular mechanism has remained elusive.Methodology/Principal FindingsUsing an unbiased transcriptomics approach, we found that cardiac glycosides inhibit general protein synthesis. Protein synthesis inhibition and cytotoxicity were not specific for cancer cells as they were observed in both primary and cancer cell lines. These effects were dependent on the Na+/K+-pump as they were rescued by expression of a cardiac glycoside-resistant Na+/K+-pump. Unlike human cells, rodent cells are largely resistant to cardiac glycosides in vitro and mice were found to tolerate extremely high levels.Conclusions/SignificanceThe physiological difference between human and mouse explains the previously observed sensitivity of human cancer cells in mouse xenograft experiments. Thus, published mouse xenograft models used to support anti-tumor activity for these drugs require reevaluation. Our finding that cardiac glycosides inhibit protein synthesis provides a mechanism for the cytotoxicity of CGs and raises concerns about ongoing clinical trials to test CGs as anti-cancer agents in humans.

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“…This peptide induces the death of a variety of transformed cells, evidenced by nucleic shrinking, DNA fragmentation, and the generation of DNA ladders [30]. Didemnin B is the first marine peptide that has been entered into human clinical trials in the USA for the treatment of cancer, and has completed phase II human clinical trials for the therapy of kidney adenocarcinoma [31], advanced epithelial ovarian cancer [32], and metastatic breast cancer [33]. The screening and development of optimal culture media for peptide SBP production from Brevibacillus sp.…”

Section: Resultsmentioning

confidence: 99%

Isolation and Characterization of Marine Brevibacillus sp. S-1 Collected from South China Sea and a Novel Antitumor Peptide Produced by the Strain

et al. 2014

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A Gram-positive, rod-shaped bacterium, designated as S-1, was isolated from a marine sediment sample collected from South China Sea. Phylogenetic analysis based on 16S rRNA gene sequence showed that S-1 belongs to the genus Brevibacillus. A novel cytotoxic peptide was isolated from the fermentation broth of the marine-derived bacterium Brevibacillus sp. S-1, using ion-exchange chromatography and reverse-phase HPLC chromatography. The molecular weight of this peptide was determined as 1570 Da by MALDI-TOF mass spectrometry, and its structure was proposed as a cyclic peptide elucidated by MALDI-TOF/TOF mass spectrometry and de novo sequencing. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay showed that this peptide exhibited cytotoxicity against BEL-7402 human hepatocellular carcinoma cells, RKO human colon carcinoma cells, A549 human lung carcinoma cells, U251 human glioma cells and MCF-7 human breast carcinoma cells. Additionally, SBP exhibited low cytotoxicity against HFL1 human normal fibroblast lung cells. The result suggested that the cytotoxic effect of the peptide is specific to tumor cells.

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Phase II trial of didemnin-B in advanced epithelial ovarian cancer

Cited by 17 publications

References 4 publications

Fate of tritiated didemnin B in mice: excretion and tissue concentrations after an intraperitoneal dose

Fate of tritiated didemnin B in mice: excretion and tissue concentrations after an intraperitoneal dose

Cardiac Glycosides Induce Cell Death in Human Cells by Inhibiting General Protein Synthesis

Isolation and Characterization of Marine Brevibacillus sp. S-1 Collected from South China Sea and a Novel Antitumor Peptide Produced by the Strain

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