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2018 ; 9
(18
): 14524-14538
Nephropedia Template TP
gab.com Text
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English Wikipedia
The circadian clock regulates cisplatin-induced toxicity and tumor regression in
melanoma mouse and human models
#MMPMID29581861
Dakup PP
; Porter KI
; Little AA
; Gajula RP
; Zhang H
; Skornyakov E
; Kemp MG
; Van Dongen HPA
; Gaddameedhi S
Oncotarget
2018[Mar]; 9
(18
): 14524-14538
PMID29581861
show ga
Cisplatin is one of the most commonly used chemotherapeutic drugs; however,
toxicity and tumor resistance limit its use. Studies using murine models and
human subjects have shown that the time of day of cisplatin treatment influences
renal and blood toxicities. We hypothesized that the mechanisms responsible for
these outcomes are driven by the circadian clock. We conducted experiments using
wild-type and circadian disrupted Per1/2(-/-) mice treated with cisplatin at
selected morning (AM) and evening (PM) times. Wild-type mice treated in the
evening showed an enhanced rate of removal of cisplatin-DNA adducts and less
toxicity than the morning-treated mice. This temporal variation in toxicity was
lost in the Per1/2(-/-) clock-disrupted mice, suggesting that the time-of-day
effect is linked to the circadian clock. Observations in blood cells from humans
subjected to simulated day and night shift schedules corroborated this view.
Per1/2(-/-) mice also exhibited a more robust immune response and slower tumor
growth rate, indicating that the circadian clock also influences the immune
response to melanoma tumors. Our findings indicate that cisplatin
chronopharmacology involves the circadian clock control of DNA repair as well as
immune responses, and thus affects both cisplatin toxicity and tumor growth. This
has important implications for chronochemotherapy in cancer patients, and also
suggests that influencing the circadian clock (e.g., through bright light
treatment) may be explored as a tool to improve patient outcomes.