In Vitro Distribution of Diacetyl Didemnin B in Human Blood Cells and Plasma

Jl, Phillips; Schwartz, Reinhard; Hoff, Von

doi:10.3109/07357908909038279

Cited by 8 publications

(2 citation statements)

References 10 publications

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“…49 LeGrue was also able to corroborate earlier work showing that didemnin B exhibits a preference for S-phase cells, suggesting a possible therapeutic application against rapidly proliferating lymphocyte or tumor cells. Phillips et al 115 used a tritiated diacetyl didemnin B derivative to show that drug uptake per cell was much higher in lymphocytes than other cells.…”

Section: B Antiproliferative Activity and Protein Biosynthesis Inhibmentioning

confidence: 99%

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: B Antiproliferative Activity and Protein Biosynthesis Inhibmentioning

confidence: 99%

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

Vera

Joullié

2002

Medicinal Research Reviews

143

109

View full text Add to dashboard Cite

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“…These authors and Hartshorn et al have used high performance liquid chromatography (HPLC) systems with detection limits of 50 m g / d (12) and 5 ng/ml, respectively (13). Dorr et al also reported the development of a radioimmunoassay (RIA) with a detection limit of 20 pg/ml (12,14); however, the antiserum required for this assay may no longer be available (Jason Fisherman, NCI, personal communication, 1990). In this study, didemnin haptens were synthesized and coupled to protein carriers for use as immunogens, and as solid phase coating antigen in enzyme-linked immunosorbent assay (ELISA) systems with anti-didemnin antibodies.…”

Section: Introductionmentioning

confidence: 99%

An enzyme immunoassay for determining plasma concentrations of didemnin B

Raybould

Grothaus

Simpson

et al. 1992

Clinical Laboratory Analysis

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Didemnin A was conjugated at the amino terminus of the N-methylleucine residue, via the linkers N-succinimidyl-3-(2-pyridyldithio)-propionate and trans-1,4-maleimidomethyl-cyclohexane carboxylic acid, to keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA). The didemnin-KLH conjugates were used to hyperimmunize rabbits. The resulting high titer antisera were employed with didemnin-BSA conjugate-coated microtiter plate wells to develop an indirect competitive inhibition enzyme immunoassay (CIEIA) that was fully cross reactive with didemnin B. A CIEIA is described that is capable of detecting the drug in plasma from didemnin B-treated patients at concentrations down to 1-3 ng/ml. This simple, sensitive CIEIA has been employed to demonstrate plasma drug clearance profiles with samples from didemnin B-treated patients.

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

et al. 1992

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Sixteen evaluable patients with metastatic breast cancer were entered into a phase II trial of didemnin B. They received the drug at an initial dose of 5.6 mg/m2 every 21 to 28 days. Major toxicities noted were myalgia and nausea and vomiting while myelosuppression was mild. There were no complete responses; however, two minor responses were observed. The pharmacokinetics of didemnin B were studied in 10 patients who received the drug as 30 to 60 min i.v. infusions. A sensitive competitive inhibition enzyme immunoassay was used to quantitate didemnin B levels. Drug was observed to be rapidly cleared from plasma in a biphasic manner (t1/2 alpha = 0.12 hr, t1/2 beta = 4.8 hr). Although the assay could not identify the presence of specific metabolites, the increase of apparent didemnin B levels in plasma at later time points suggested the formation of unidentified metabolites which cross reacted with the antibody in the analytical procedure. In vitro experiments indicated that didemnin B was not bound to bovine serum albumin and only a minor portion (24%) of drug was found associated with red blood cells.

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In Vitro Distribution of Diacetyl Didemnin B in Human Blood Cells and Plasma

Cited by 8 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

An enzyme immunoassay for determining plasma concentrations of didemnin B

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

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