Phase II clinical and pharmacological study of didemnin B in patients with metastatic breast cancer

Benvenuto, John A.; Newman, Robert A.; Bignami, Gary S.; Raybould, T. J. G.; Raber, Martin N.; Esparza, Laura; Walters, Ronald S.

doi:10.1007/bf00873128

Cited by 34 publications

(17 citation statements)

References 10 publications

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“…The notion of improved therapeutic ef®cacy in a continuous exposure regime is also consistent with the report by Benvenuto et al 21 showing that didemnin B undergoes rapid clearance in vivo. Given the authors' determination of a circulating half-life for didemnin B of less than 5 hr, it is possible to speculate that the poor ef®cacy shown in Phase II trials might be due to the dose schedules used.…”

Section: C L I N I C a L T R I A L Ssupporting

confidence: 76%

“…Because of the poor clinical performance and limited biological half-life of didemnins in vivo, 21 there has been some focus on the replacement of the macrocyclic ester bonds of didemnins. The ®rst example of such an analog was reported by Katauskas and Rinehart 108 in which the ester bond between Hip 2 and Ist 1 ( Fig.…”

Section: Modi®cations To the Macrocyclic Backbonementioning

confidence: 99%

“…62,63 In another Phase I study conducted by Maroun et al 64 without an anti-emetic treatment, nausea and vomiting were dose-limiting at 1.2 mg/m 2 . During a Phase II study reported by Benvenuto et al 21 in 1992, the pharmacokinetics of didemnin B were studied in 10 patients who received infusions of the drug lasting 30±60 min. An enzyme immunoassay was used to quantitate the drug, and showed rapid biphasic clearance from plasma with apparent half-lives of 0.12 and 4.8 hr.…”

Section: C L I N I C a L T R I A L Smentioning

confidence: 99%

“…8 This result suggests that the ester linkage between N,O-Me 2 Tyr 5 and Thr 6 is especially susceptible to degradation. A rapid but unspeci®ed degradation of didemnin B during clinical trials was reported by Benvenuto et al, 21 a ®nding which could have signi®cant implications for clinical applications of didemnins. An additional possibility is that the acyclic compound is a biosynthetic precursor.…”

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confidence: 91%

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Natural products as probes of cell biology: 20 years of didemnin research

Vera

Joullié

2002

Medicinal Research Reviews

143

109

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The discovery of the didemnin family of marine depsipeptides launched an exciting and intriguing chapter in natural product chemistry. The unusual structure of the didemnin congeners has led to several total syntheses by research groups from around the world. The impressive in vitro and in vivo biological activities of the didemnins resulted in the first human clinical trials in the U.S. of a marine natural product against cancer, and additional clinical trials of a second-generation didemnin, dehydrodidemnin B (aplidine), are underway. As we mark the 20-year anniversary of the discovery of the didemnins, this class of natural products continues to stimulate active research in fields ranging from synthetic and medicinal chemistry to clinical oncology and cell biology. While some progress was made in dissecting the molecular mechanism of action and in establishing structure-activity relationships, there are still more questions than answers. This review covers the recent didemnin literature, highlighting the work directed towards understanding how this group of natural products interact with fundamental processes such as cell proliferation, protein biosynthesis, and apoptosis. The didemnin field illustrates how natural product chemistry may be used as a critical tool for the study of cell biology.

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Section: C L I N I C a L T R I A L Ssupporting

confidence: 76%

Section: Modi®cations To the Macrocyclic Backbonementioning

confidence: 99%

Section: C L I N I C a L T R I A L Smentioning

confidence: 99%

mentioning

confidence: 91%

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Natural products as probes of cell biology: 20 years of didemnin research

Vera

Joullié

2002

Medicinal Research Reviews

143

109

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“…A trial with cancer patients revealed biphasic clearance from plasma, with a t 1/2 a of 0.12 h, and a t 1/2 b of 4.8 h [32]. This study characterized elimination, tissue concentrations and metabolism of tritiated didemnin B over time using male mice dosed i.p..…”

Section: Introductionmentioning

confidence: 97%

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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Phase II clinical trial of didemnin B in previously treated small cell lung cancer

et al. 1994

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Didemnin B (NSC 325319), a cyclic depsipeptide isolated from a Carribean sea tunicate, exhibited potent antitumor activity in preclinical studies. After determining the maximum tolerated dose in our previous phase I/II trial, we conducted a phase II study of this drug in patients with previously treated small cell lung cancer; the starting dose was 6.3 mg/m2 intravenously over 30 min every 28 days. The major side effects were in the neuromuscular system and included severe muscle weakness, myopathy and/or myotonia by electromyography, and elevation of creatine phosphokinase and aldolase levels. We also observed modest increases in bilirubin and alkaline phosphatase levels. There were minimal hematologic toxic effects. No response was observed among 15 evaluable patients, leading us to conclude that didemnin B was toxic but inactive in patients with previously treated small cell lung cancer at the stated dose and schedule. A review of the literature revealed no significant antitumor activity in cancers of the colon, breast, ovaries, cervix, or lung (non-small cell) or in renal cell carcinoma. Further clinical trials for didemnin B may not be warranted at the stated dose and schedule.

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Phase II clinical and pharmacological study of didemnin B in patients with metastatic breast cancer

Cited by 34 publications

References 10 publications

Natural products as probes of cell biology: 20 years of didemnin research

Natural products as probes of cell biology: 20 years of didemnin research

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

Phase II clinical trial of didemnin B in previously treated small cell lung cancer

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