ArticleToxicology and applied pharmacology2014
Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities.
Article in Toxicology and applied pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- The Use of Bacteria and Their Toxins as Antitumor Agents: Present and Future.Microorganisms · 2026Review
- Article
- Natural and Designed Toxins for Precise Therapy: Modern Approaches in Experimental Oncology.International journal of molecular sciences · 2021Review
- Article
- Article
- Cell surface-anchored serine proteases in cancer progression and metastasis.Cancer metastasis reviews · 2019Review
- Bismaleimide cross-linked anthrax toxin forms functional octamers with high specificity in tumor targeting.Protein science : a publication of the Protein Society · 2019Article
- Anthrax lethal toxin rapidly reduces c-Jun levels by inhibiting c-Jun gene transcription and promoting c-Jun protein degradation.The Journal of biological chemistry · 2017Article
- Functional classification of protein toxins as a basis for bioinformatic screening.Scientific reports · 2017Article
- Solid tumor therapy by selectively targeting stromal endothelial cells.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- The Ins and Outs of Anthrax Toxin.Toxins · 2016Review
- An anthrax toxin variant with an improved activity in tumor targeting.Scientific reports · 2015Article
- Targeting the membrane-anchored serine protease testisin with a novel engineered anthrax toxin prodrug to kill tumor cells and reduce tumor burden.Oncotarget · 2015Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5-3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.