The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 258

treatments would inevitably have an adverse effect on patients. Biological pro-
cesses determining the efficiency of anticancer drugs including drug absorp-
tion, distribution, intracellular metabolism, and elimination follow circadian
rhythms in the host. 475 In addition, once inside the tumor cells, the function
of a cytotoxic drug is largely determined by the circadian phase of cell prolif-
eration in the tumors, which, even in advanced stage tumors, is not temporally
disorganized. 211,216-220,476 Therefore, to apply anticancer treatment at a
selected time during the day based on circadian variation in host internal phys-
iology and the asynchronies in cell proliferation and drug metabolic rhythms
between normal andmalignant tissues couldmaximize drug toxicity to tumors
and increase the efficiency of anticancer treatment. 477
Studies using mouse models have revealed that both host tolerability and
drug efficacy are affected by circadian timing, and that the best therapeutic
index is achieved by coupling the time for drug delivery with host endog-
enous circadian rhythms. 478 These results have been extrapolated to ran-
domized clinical trials of patients undergoing treatment for advanced
stage cancers including metastatic ovarian, lung, colorectal, and breast can-
cers using conventional chemotherapeutic drugs. 58,479,480 The results of
these studies have revealed that current procedures of anticancer chrono-
therapy indeed leads to better therapeutic outcomes and is especially more
beneficial to patients who still maintain the endogenous circadian rhythmic-
ity. The improved therapeutic index is shown by reduced drug toxicity,
improved tumor response rate and the duration of the response, and
decreased frequency of tumor metastasis. However, although chronother-
apy has been shown to significantly increase the survival time for children
with ALL, 481 it does not increase the long-term survival of patients with
metastasizing cancers, 187 suggesting that anticancer chronotherapy is still
at its initial stage of practice and needs further improvement. The facts that
the molecular clock directly responds to genotoxic insults and that mice
deficient in the Clock , Bmal1 , and Cry genes respond differently to anticancer
drugs compared to wild-type controls suggest that the response to anticancer
treatment is a complicated clock-controlled physiological function
in vivo . 124,182,260,261 Further investigation of the mechanisms of cancer chro-
notherapy, especially the mechanisms controlling the response of the circa-
dian clock to anticancer treatment, the consequence of such a response for
host physiology and tumor biology, the effect of tumor development on host
circadian homeostasis, and the ability of the clock to respond to anticancer
treatment would contribute greatly to improve the current anticancer
chronotherapy.