Potentiation of metalloenediyne cytotoxicity by hyperthermia

Enediynes are potent inducers of DNA damage, but their clinical usefulness has been limited. Here we report the thermal enhancement of cytotoxicity of two novel metalloenediyne compounds at concentrations that are either not or minimally cytotoxic at 37°C, and present evidence regarding possible mec...

Full description

Saved in:

Bibliographic Details
Published in:	International journal of hyperthermia Vol. 27; no. 5; p. 435
Main Authors:	Routt, Stefan M, Zhu, Ju, Zaleski, Jeffrey M, Dynlacht, Joseph R
Format:	Journal Article
Language:	English
Published:	England 01-08-2011
Subjects:	Apoptosis - drug effects Cell Cycle - drug effects Cell Survival Combined Modality Therapy Coordination Complexes - toxicity Drug Synergism Enediynes - toxicity HeLa Cells Hot Temperature Humans Hyperthermia, Induced Organometallic Compounds - toxicity Pyridines - toxicity
Online Access:	Get more information
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Enediynes are potent inducers of DNA damage, but their clinical usefulness has been limited. Here we report the thermal enhancement of cytotoxicity of two novel metalloenediyne compounds at concentrations that are either not or minimally cytotoxic at 37°C, and present evidence regarding possible mechanisms for enhanced cytotoxicity. HeLa cells were exposed to (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine (PyED) (which becomes metallated in culture medium) or ((Z)-N,N'-bis[quinolin-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine)zinc(II) chloride (QuinED · ZnCl(2)) at 37°C or 42.5°C for 1 h, and clonogenic survival was compared after treatment at each temperature. Analyses of cell cycle progression and mode of death were performed after treatments. Treatment with PyED or QuinED · ZnCl(2) resulted in a significant decrease in cell survival when cells were treated with drug at 42.5°C compared to 37°C. Enhanced cytotoxicity was attributed to increased apoptosis. However, perturbation of the cell cycle may also play a role. Cells which were only heated or exposed to PyED at 37°C experienced significant G(2)/M blocks that were eliminated when PyED and heat were administered simultaneously, suggesting that combined treatments override cell cycle arrests normally observed with each agent individually. Conversely, cells heated during treatment with QuinED · ZnCl(2) displayed an increased G(2)/M arrest compared to treatment at 37°C. With improvements in site-specific heat delivery to tumours, systemic administration of non-toxic metalloenediynes coupled with localised hyperthermia may improve selective enediyne activation/targeting. Therefore PyED and QuinED · ZnCl(2), which show significantly enhanced cytotoxicity at elevated temperatures, may represent viable candidates for thermochemotherapy.
ISSN:	1464-5157
DOI:	10.3109/02656736.2011.578607