A Comparison of the Inhibitory Effects of Immunosuppressive Agents Cyclosporine, Tetranactin, and Didemnin B on Human T Cell Responses in Vitro

Teunissen, Marcel B. M.; Pistoor, F.H.M.; Rongen, H.A.H.; Kapsenberg, Martien L.; Bos, Jan D.

doi:10.1097/00007890-199204000-00031

Cited by 22 publications

(15 citation statements)

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“…Teunissen et al 54 compared the in vitro inhibition potencies of CsA, didemnin B, and tetranactin (TN) against human T-cell proliferation in vitro. Didemnin B was shown to be the most potent drug tested (IC 50 1±4 ng/ml) while CsA and TN were about tenfold less active (IC 50 50± 60 ng/ml).…”

Section: ±46mentioning

confidence: 99%

“…The results showed that human T-cell proliferation was far less sensitive to inhibition by didemnin B than the mouse model used by Montgomery et al Didemnin B was also shown to be toxic at the 10 ng/ml level, while CsA and TN were non-toxic at doses up to 5,000 ng/ml. Teunissen et al 54 noted that the earlier claim by Montgomery et al, 47 that didemnin B was 100 to 1,000-fold more potent than CsA, relied upon a comparison of results in mice for didemnin B with results in man for CsA. They cautioned that comparison between different test systems was unreliable.…”

Section: ±46mentioning

confidence: 99%

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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: ±46mentioning

confidence: 99%

Section: ±46mentioning

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 macrotetrolides exert a broad spectrum of biological activities (56), ranging from antibacterial, antifungal, antitumor (11), antiprotozoan, antiparasitic, and insecticidal activities to immunosuppressive activities (12,(47)(48)(49)56). In fact, comparative studies on the immunosuppressive activities of tetranactin and cyclosporin, the latter being the most widely used immunosuppressant agent, showed that these two compounds were approximately equally effective and that tetranactin has the advantage of low toxicity (49).…”

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confidence: 99%

“…In fact, comparative studies on the immunosuppressive activities of tetranactin and cyclosporin, the latter being the most widely used immunosuppressant agent, showed that these two compounds were approximately equally effective and that tetranactin has the advantage of low toxicity (49). The biological activities of the macrotetrolides are generally traced to their ionophoric properties (30,38,46), and the potencies of these activities appear to parallel the size of the alkyl substituents of the macrotetrolides: tetranactin is often the most potent member of the family, while NON is generally inactive.…”

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Genetic Localization and Molecular Characterization of the nonS Gene Required for Macrotetrolide Biosynthesis in Streptomyces griseus DSM40695

Smith

Xiang

Shen

2000

Antimicrob Agents Chemother

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The macrotetrolides are a family of cyclic polyethers derived from tetramerization, in a stereospecific fashion, of the enantiomeric nonactic acid (NA) and its homologs. Isotope labeling experiments established that NA is of polyketide origin, and biochemical investigations demonstrated that 2-methyl-6,8-dihydroxynon-2E-enoic acid can be converted into NA by a cell-free preparation from Streptomyces lividans that expresses nonS. These results lead to the hypothesis that macrotetrolide biosynthesis involves a pair of enantiospecific polyketide pathways. In this work, a 55-kb contiguous DNA region was cloned from Streptomyces griseus DSM40695, a 6.3-kb fragment of which was sequenced to reveal five open reading frames, including the previously reported nonR and nonS genes. Inactivation of nonS in vivo completely abolished macrotetrolide production. Complementation of the nonS mutant by the expression of nonS in trans fully restored its macrotetrolide production ability, with a distribution of individual macrotetrolides similar to that for the wild-type producer. In contrast, fermentation of the nonS mutant in the presence of exogenous (؎)-NA resulted in the production of nonactin, monactin, and dinactin but not in the production of trinactin and tetranactin. These results prove the direct involvement of nonS in macrotetrolide biosynthesis. The difference in macrotetrolide production between in vivo complementation of the nonS mutant by the plasmid-borne nonS gene and fermentation of the nonS mutant in the presence of exogenously added (؎)-NA suggests that NonS catalyzes the formation of (؊)-NA and its homologs, supporting the existence of a pair of enantiospecific polyketide pathways for macrotetrolide biosynthesis in S. griseus. The latter should provide a model that can be used to study the mechanism by which polyketide synthase controls stereochemistry during polyketide biosynthesis.

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“…As for cyclosporin A, strong immunosuppressive activity has been reported for tetranactin Teunissen et al, 1992). Tetranactin has been shown to block the proliferation of T-lymphocytes as well as the generation of cytotoxic T-lymphocytes and activated killer cells (Callewaert et al, 1988).…”

Section: Introductionmentioning

confidence: 99%