Disease relevance of Didemnin B

• The active compounds isolated from the tunicate, didemnins A, B, and C, are depsipeptides, and didemnin B (a derivative of didemnin A) is the component active at the lowest concentration in inhibiting viral replication in vitro and P388 leukemia in vivo [1].
• Prolactin (PRL)-stimulated ornithine decarboxylase (ODC) activity and subsequent proliferation are inhibited by the cyclopeptides cyclosporine (CsA) and didemnin B (DB) in Nb 2 node lymphoma cells [2].
• S. National Cancer Institute, indicated complete or partial remissions with non-Hodgkins lymphoma, but cardiotoxicity caused didemnin B to be dropped from further study [3].
• Nordidemnin (2), a natural analogue of the marine cyclodepsipeptide didemnin B (1b), showed cytotoxic activity against L1210 leukemia and antineoplastic activity against P388 leukemia as well as B16 melanoma; nordidemnin (2) was as active as didemnin B (1b) [4].
• The agents cyclosporine, tetranactin (TN), and didemnin B (DB) were compared for their ability to inhibit proliferative human T cell responses in vitro, using anti-CD3, PHA, alloantigen, or tetanus toxoid as stimuli and using monocytes or Langerhans cells as antigen-presenting cells/accessory cells (APC/AC) [5].

Psychiatry related information on Didemnin B

• Fluorescent analogues (DB1 and TA1) of the secondary metabolites didemnin B (DB) and tamandarin A (TA) were synthesized to investigate the potential chemical defense mechanisms of tunicates in the family Didemnidae [6].

High impact information on Didemnin B

• Our initial investigation of didemnin B resulted in the discovery of its GTP-dependent binding of the translation elongation factor EF1 alpha [7].
• Mitotic cells were the least sensitive to didemnin B, and cells became more sensitive as they progressed into G1 and S phase [8].
• Didemnin B inhibited the in vitro growth of B16 greater than L1210 greater than V-79 cells = human foreskin fibroblast = 9L greater than Chinese hamster ovary cells [8].
• The marine natural product, didemnin B, is a 7-amino acid, cyclic depsipeptide that inhibits G1 cell cycle progression at nanomolar concentrations by undefined mechanisms [9].
• Addition of CsA or DB 2 hr after PRL had no effect on PRL-stimulated ODC activity detectable at 6 hr, but addition of either as late as 6 hr still affected the extent of mitogenesis [2].

Chemical compound and disease context of Didemnin B

• The [N,O-Me(2)Tyr(5)]residue of didemnin B was replaced with L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) and L-1,2,3,4-tetrahydro-7-methoxyisoquinoline-3-carboxylic acid (MeO-Tic), which mimic the N,O-dimethylated tyrosine while constraining the conformation of the molecule [10].
• A randomized phase II trial of trimetrexate or didemnin B for the treatment of metastatic or recurrent squamous carcinoma of the uterine cervix: a Southwest Oncology Group trial [11].

Biological context of Didemnin B

• Induction of apoptosis by didemnin B in cultured human pro-myeloid HL-60 cells is the fastest and most complete ever described with all cells being apoptotic after 3 h of treatment [12].
• Because continued production of mature leukocytes by bone marrow and an intact antibody response are crucial to defense against infection in immunosuppressed patients, we have evaluated the effects of DB on these processes as well [13].
• The pharmacokinetics of didemnin B were studied in 10 patients who received the drug as 30 to 60 min i.v. infusions [14].
• Didemnin B in favourable histology non-Hodgkin's lymphoma. A phase II study of the National Cancer Institute of Canada Clinical Trials Group [15].
• RESULTS: Didemnin B and - especially - Aplidine were more effective in the inhibition of prostate cancer cell proliferation than vincristine, vinorelbine or Taxol at concentration levels between 5 and 50 pmol/ml [16].

Anatomical context of Didemnin B

• Didemnin B, a branched cyclic peptolide described to have immunosuppressive, anti-tumour, and anti-viral properties, induces rapid apoptosis in a range of mammalian cell lines [12].
• 3H-thymidine incorporation (4 hr) by freshly harvested bone marrow leukocytes from DB-treated mice (0.025, 0.05, and 0.10 mg/kg/day x 7 days) was enhanced up to 40% over control (P less than .05), while bone marrow cellularity was increased 200% (P less than .01).(ABSTRACT TRUNCATED AT 400 WORDS)[13]
• Anti-sheep red blood cell (SRBC) hemagglutinating antibody (hAb) production was induced by i.p. injection of 5 x 10(7) SRBC in CB6F1 mice (5/group) treated with vehicle or DB once/day for six days [13].
• Didemnin B (DB) is a 7-amino-acid, cyclic polypeptide with potent (10(7)-10(10)M) antiproliferative effects in vivo and in vitro against a variety of viruses and tumor cell lines [17].
• Kinetic studies showed that by 24 hr after a single i.p. injection of DB (1.0 mg/kg), blood leukocyte, granulocyte, and lymphocyte counts were elevated by 2.5-, 3-, and 2-fold, respectively, but declined rapidly thereafter [13].

Associations of Didemnin B with other chemical compounds

• These observations suggest that didemnin B prevents translocation by stabilizing aminoacyl-tRNA bound to the ribosomal A-site, similar to the antibiotic kirromycin, and consistent with the known affinity of didemnins for elongation factor eEF-1 alpha [Crews et al. (1994) J. Biol. Chem. 269, 15411] [18].
• Unlike kirromycin, didemnin B does not prevent peptide bond formation, so inhibition is observed only at the translocation step [18].
• Nordidemnin (NorD), a cyclodepsipeptide isolated from marine invertebrates, exhibits antiproliferative and antitumoral properties identical to didemnin B on many cell lines [19].
• In vitro distribution of diacetyl didemnin B in human blood cells and plasma [20].
• With the brush border membrane vesicles prepared from the rat kidney cortex, didemnin B and its parent compound, didemnin A function neither as a K+-specific ionophore nor as an ionophore for Na+ ions while other depsipeptide antibiotics such as valinomycin and gramicidin promote transmembrane movement of K+ and Na+ ions, respectively [21].

Gene context of Didemnin B

• Inhibition of T-lymphocyte proliferation by the cyclic polypeptide didemnin B: no inhibition of lymphokine stimulation [22].
• The lack of competition for rapamycin-mediated inhibition of didemnin B-induced apoptosis by FK506 suggests that rapamycin inhibits apoptosis through some mechanism other than inhibition of p70 S6 kinase activation [23].
• Kinetic analysis of this inhibition revealed that didemnin B inhibits PPT1 uncompetitively [24].
• Mitochondrial cytochrome c release is caspase-dependent and does not involve mitochondrial permeability transition in didemnin B-induced apoptosis [12].
• Thirteen patients were treated with didemnin B at 3.5 mg/m2 and 20 patients were treated at 6.3 mg/m2 intravenously every 28 days [25].

Analytical, diagnostic and therapeutic context of Didemnin B

• The marine natural product didemnin B, currently in clinical trials as an antitumor agent, has several potent biological activities apparently mediated by distinct mechanisms [7].
• Prolongation of skin allograft survival in mice by didemnin B [26].
• A sensitive competitive inhibition enzyme immunoassay was used to quantitate didemnin B levels [14].
• Ten patients with previously untreated stage III/IV low grade histology non-Hodgkin's lymphoma received a 1-hour intravenous infusion of Didemnin B 2.3 mg/m2 weekly for 4 weeks repeated every 6 weeks [15].
• Didemnin B administered at a dose of 0.06 mg/kg, highest nontoxic dose for the rat, shows a high antitumor activity against Yoshida ascites tumor only after intraperitoneal injection of the drug; supplied by other routes both against T8 sarcoma of Guérin and Yoshida ascites tumor is ineffective [27].

References