Characterization and initial demonstration of in vivo efficacy of a novel heat-activated metalloenediyne anti-cancer agent

Enediynes are anti-cancer agents that are highly cytotoxic due to their propensity for low thermal activation of radical generation. The diradical intermediate produced from Bergman cyclization of the enediyne moiety may induce DNA damage and cell lethality. The cytotoxicity of enediynes and difficu...

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Published in:	International journal of hyperthermia Vol. 39; no. 1; pp. 405 - 413
Main Authors:	Garrett, Joy, Metzger, Erin, Dewhirst, Mark W., Pollok, Karen E., Turchi, John J., Le Poole, Isabelle C., Couch, Kira, Lew, Logan, Sinn, Anthony, Zaleski, Jeffrey M., Dynlacht, Joseph R.
Format:	Journal Article
Language:	English
Published:	England Taylor & Francis 2022 Taylor & Francis Group
Subjects:	Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Cyclization Enediynes - chemistry Enediynes - pharmacology Enediynes - therapeutic use Hot Temperature Humans hyperthermia Hyperthermia, Induced melanoma Metalloenediyne Mice thermal ablation thermal activation Metalloenediyne melanoma hyperthermia thermal activation thermal ablation
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Summary:	Enediynes are anti-cancer agents that are highly cytotoxic due to their propensity for low thermal activation of radical generation. The diradical intermediate produced from Bergman cyclization of the enediyne moiety may induce DNA damage and cell lethality. The cytotoxicity of enediynes and difficulties in controlling their thermal cyclization has limited their clinical use. We recently showed that enediyne toxicity at 37 °C can be mitigated by metallation, but cytotoxic effects of 'metalloenediynes' on cultured tumor cells are potentiated by hyperthermia. Reduction of cytotoxicity at normothermia suggests metalloenediynes will have a large therapeutic margin, with cell death occurring primarily in the heated tumor. Based on our previous in vitro findings, FeSO 4 -PyED, an Fe co-factor complex of (Z)-N,N′-bis[1-pyridin-2-yl-meth-(E)-ylidene]oct-4-ene-2,6-diyne-1,8-diamine, was prioritized for further in vitro and in vivo testing in normal human melanocytes and melanoma cells. Clonogenic survival, apopotosis and DNA binding assays were used to determine mechanisms of enhancement of FeSO 4 -PyED cytotoxicity by hyperthermia. A murine human melanoma xenograft model was used to assess in vivo efficacy of FeSO 4 -PyED at 37 or 42.5 °C. FeSO 4 -PyED is a DNA-binding compound. Enhancement of FeSO 4 -PyED cytotoxicity by hyperthermia in melanoma cells was due to Bergman cyclization, diradical formation, and increased apoptosis. Thermal enhancement, however, was not observed in melanocytes. FeSO 4 -PyED inhibited tumor growth when melanomas were heated during drug treatment, without inducing normal tissue damage. By leveraging the unique thermal activation properties of metalloenediynes, we propose that localized moderate hyperthermia can be used to confine the cytotoxicity of these compounds to tumors, while sparing normal tissue.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	0265-6736 1464-5157
DOI:	10.1080/02656736.2021.2024280