Characterization and initial demonstration of in vivo efficacy of a novel heat-activated metalloenediyne anti-cancer agent. (31st December 2022)

• Record Type: Journal Article
• 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.
• Is Part Of: International journal of hyperthermia. Volume 39:Number 1(2022)
• Page Start: 405
• Page End: 413
• Publication Date: 2022-12-31
• Subjects: Metalloenediyne -- melanoma -- thermal activation -- hyperthermia -- thermal ablation; Thermotherapy -- Periodicals; 615.832
• DOI: 10.1080/02656736.2021.2024280
• Languages: English
• ISSNs: 0265-6736

Abstract

Abstract: Background: 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, FeSO4 -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. Methods: Clonogenic survival, apopotosis and DNA binding assays were used to determine mechanisms of enhancement of FeSO4 -PyED cytotoxicity by hyperthermia. A murine human melanoma xenograft model was used to assess in vivo efficacy of FeSO4 -PyED at 37 or 42.5 °C. Results: FeSO4 -PyED is a DNA-binding compound. Enhancement of FeSO4 -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. FeSO4 -PyED inhibited tumor growth when melanomas were heated during drug treatment, without inducing normal tissue damage. Conclusion: 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.