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2013 ; ä (217
): 289-309
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Pharmacological modulators of the circadian clock as potential therapeutic drugs:
focus on genotoxic/anticancer therapy
#MMPMID23604484
Antoch MP
; Kondratov RV
Handb Exp Pharmacol
2013[]; ä (217
): 289-309
PMID23604484
show ga
The circadian clock is an evolutionary conserved intrinsic timekeeping mechanism
that controls daily variations in multiple biological processes. One important
process that is modulated by the circadian clock is an organism's response to
genotoxic stress, such as that induced by anticancer drug and radiation
treatments. Numerous observations made in animal models have convincingly
demonstrated that drug-induced toxicity displays prominent daily variations;
therefore, undesirable side effects could be significantly reduced by
administration of drugs at specific times when they are better tolerated. In some
cases, these critical times of the day coincide with increased sensitivity of
tumor cells allowing for a greater therapeutic index. Despite encouraging results
of chronomodulated therapies, our knowledge of molecular mechanisms underlying
these observations remains sketchy. Here we review recent progress in deciphering
mechanistic links between circadian and stress response pathways with a focus on
how these findings could be applied to anticancer clinical practice. We discuss
the potential for using high-throughput screens to identify small molecules that
can modulate basic parameters of the entire circadian machinery as well as
functional activity of its individual components. We also describe the discovery
of several small molecules that can pharmacologically modulate clock and that
have a potential to be developed into therapeutic drugs. We believe that
translational applications of clock-targeting pharmaceuticals are twofold: they
may be developed into drugs to treat circadian-related disorders or used in
combination with existing therapeutic strategies to improve therapeutic index of
a given genotoxic treatment via the intrinsic clock mechanism.
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