Echinomycin: The first bifunctional intercalating agent in clinical trials

Foster, Brenda J.; Clagett-Carr, K; Shoemaker, DeWayne; Suffness, Matthew; Plowman, Jacqueline; Trissel, Lawrence A.; Grieshaber, Charles K.; Leyland‐Jones, Brian

doi:10.1007/bf00170766

Cited by 58 publications

(46 citation statements)

References 9 publications

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“…NSC-13502 was brought into clinical trials by the NCI 20 years ago based on its antitumor activity against two i.p. implanted murine tumors, the B16 melanoma and the P388 leukemia (47). NSC-13502, at 1.2 to 1.5 mg/m 2 once weekly for 4 weeks or once every 3 to 4 weeks (47-50), has been extensively tested in phase I-II clinical trials.…”

Section: Resultsmentioning

confidence: 99%

Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity

et al. 2005

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The identification of small molecules that inhibit the sequencespecific binding of transcription factors to DNA is an attractive approach for regulation of gene expression. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that controls genes involved in glycolysis, angiogenesis, migration, and invasion, all of which are important for tumor progression and metastasis. To identify inhibitors of HIF-1 DNA-binding activity, we expressed truncated HIF-1A and HIF-1B proteins containing the basichelix-loop-helix and PAS domains. Expressed recombinant HIF-1A and HIF-1B proteins induced a specific DNA-binding activity to a double-stranded oligonucleotide containing a canonical hypoxia-responsive element (HRE). One hundred twenty-eight compounds previously identified in a HIF-1-targeted cell-based high-throughput screen of the National Cancer Institute 140,000 small-molecule library were tested in a 96-well plate ELISA for inhibition of HIF-1 DNA-binding activity. One of the most potent compounds identified, echinomycin (NSC-13502), a smallmolecule known to bind DNA in a sequence-specific fashion, was further investigated. Electrophoretic mobility shift assay experiments showed that NSC-13502 inhibited binding of HIF-1A and HIF-1B proteins to a HRE sequence but not binding of the corresponding proteins to activator protein-1 (AP-1) or nuclear factor-KB (NF-KB) consensus sequences. Interestingly, chromatin immunoprecipitation experiments showed that NSC-13502 specifically inhibited binding of HIF-1 to the HRE sequence contained in the vascular endothelial growth factor (VEGF) promoter but not binding of AP-1 or NF-KB to promoter regions of corresponding target genes. Accordingly, NSC-13502 inhibited hypoxic induction of luciferase in U251-HRE cells and VEGF mRNA expression in U251 cells. Our results indicate that it is possible to identify small molecules that inhibit HIF-1 DNA binding to endogenous promoters. (Cancer Res 2005; 65(19): 9047-55)

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Section: Resultsmentioning

confidence: 99%

Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity

et al. 2005

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“…In light of excellent antitumour activity and tolerable toxicity in preclinical and Phase 1 trials, echinomycin has been used in a Phase II clinical trial for the treatment of solid types of cancer such as colon cancer and ovarian cancer. 25,26 Therefore, we investigated in vivo applicability.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo activities of echinomycin against clinical isolates of Staphylococcus aureus

Park

Shin

Kim

2007

Journal of Antimicrobial Chemotherapy

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Objectives: To verify in vitro and in vivo activities of echinomycin against clinical isolates of Staphylococcus aureus, we compared antistaphylococcal activities of echinomycin with those of vancomycin.Methods: In vitro activities (MICs and MBCs) of oxacillin, vancomycin and echinomycin against 18 isolates of methicillin-susceptible S. aureus (MSSA) and 118 isolates of methicillin-resistant S. aureus (MRSA) were compared. Using four representative isolates of S. aureus, time-kill assay and in vivo antistaphylococcal activities were assessed. Echinomycin and vancomycin were compared in an in vivo mouse infection model.Results: Echinomycin demonstrated higher in vitro activities against MSSA and MRSA strains, exhibiting 2-fold lower MIC 90 s and 4-fold lower MBC 90 s than vancomycin. Additionally, time-kill assay indicated that echinomycin is more potent than vancomycin against MSSA and MRSA strains in the context of MICs and MBCs. Using an in vivo protection model, it was shown that the 50% effective doses of echinomycin were at least 7-fold lower than those of vancomycin. Therefore, echinomycin displayed excellent protection in mice against acute peritoneal infections caused by both MSSA and MRSA strains.Conclusions: Collectively, these data indicate that the activity of echinomycin against S. aureus strains is at least equivalent to that of vancomycin, regardless of the methicillin resistance of these strains. These promising activities of echinomycin might justify its potential use against infections with S. aureus strains resistant to vancomycin. This might be the first report to show that echinomycin possesses antipathogenic staphylococcal activity.

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“…over 15 minutes after cisplatin and etoposide 120 tumor models. 8 Trimetrexate is a potent inhibitor of dihydrofolate mg/m 2 /day on Days 1 -3 in 250 cc of normal saline i.v. over 45 minutes.…”

Section: Treatment Planmentioning

confidence: 99%

A randomized Phase II trial of echinomycin, trimetrexate, and cisplatin plus etoposide in patients with metastatic nonsmall cell lung carcinoma

Chang¹,

Kim

Boucher

et al. 1998

Cancer

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Echinomycin: The first bifunctional intercalating agent in clinical trials

Cited by 58 publications

References 9 publications

Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity

Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity

In vitro and in vivo activities of echinomycin against clinical isolates of Staphylococcus aureus

A randomized Phase II trial of echinomycin, trimetrexate, and cisplatin plus etoposide in patients with metastatic nonsmall cell lung carcinoma

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