February 01, 2005
Effective Cancer Treatments Follow the Clock
Oncologists have long thought that cancer treatments tend to be more
effective at certain times of day. But they have been unable to turn
this knowledge into practice, because they did not understand the
phenomenon well enough. Now, researchers have discovered a molecular
mechanism that explains why sensitivity to anti-cancer drugs changes
with the clock. They said their findings could lead to new drug
treatments that may be more effective because they harness the power
and precision of the body's internal clock.
The research team, which included senior author Joseph S. Takahashi,
a Howard Hughes Medical Institute investigator at Northwestern
University, and senior author Marina P. Antoch at the Cleveland Clinic
Lerner Research Institute in Cleveland, Ohio, published its findings
February 1, 2005, in the early online edition of the Proceedings of
the National Academy of Sciences.
“This is not some vague metabolic difference between day and night. This is a tangible difference in the immune system that influences sensitivity.”
Joseph S. Takahashi
In experiments, which were conducted in mice, the scientists found
that the body's internal biological clock affects the survival of
immune cells that are targets of the anti-cancer drug cyclophosphamide
(CY).
“We became interested in examining this issue because there is
a long history of knowledge that chemotherapeutic agents produce
different mortality and morbidity at different times of the day,”
said Takahashi. The initial experiments with normal mice, performed by
Antoch during her tenure in Takahashi's lab, confirmed that animals
treated with CY survived better when they received treatment in late
afternoon than those whose treatments were initiated early in the
morning. Antoch further extended these original findings after she
moved to Cleveland and established her research program in the
Department of Cancer Biology at the Cleveland Clinic Foundation.
To examine the mechanism for this difference, Antoch and her
colleagues used mice that genetically lack different components of the
body's internal clock. “Knowing the molecular mechanism of
internal clock function lets us make some important predictions of how
these mice may respond to drug treatment,” said Antoch.
“Thus, defects in Clock or Bmal1 genes, which
essentially damp the cycles of the internal clock may produce very
different effect when compared to defects in Cryptochrome gene,
which, in contrast, `jams' the circadian clock at the most active point
in its cycle.”
Biological clocks function in the brain as well as lung, liver,
heart and skeletal muscles. They operate on a 24-hour, circadian (Latin
for "about a day") cycle that governs functions like sleeping and
waking, rest and activity, fluid balance, body temperature, cardiac
output, oxygen consumption and endocrine gland secretion.
In their experiments, the researchers measured the animals' body
weight as an indicator of response to the anti-cancer drug. They
discovered that Clock-mutant and Bmal1-knockout mice
showed high sensitivity to the drug at any time it was administered —
as if the drug were administered early in the morning or late at night.
In contrast, the Cryptochrome knockout mice showed more
resistance to the drug at all times than did normal mice.
The researchers then tested whether this effect might be due to
differences in the metabolic activation of the anti-cancer drug, but
found essentially none. “This was a real surprise, because some
of the enzymes involved in activating CY in the liver show circadian
rhythms,” said Takahashi. “We thought that the liver might
be activating the drug more strongly at some times, or detoxifying it
less effectively, or both.”
However, when the researchers analyzed the activity of the knockout
animals' immune system B cells, they found evidence that the activity
of the Clock and Bmal1 genes determined the cells'
sensitivity to CY.
“Thus, this paper gives us specific mechanistic insight into
the role of circadian rhythms in sensitivity to such drugs,” said
Takahashi. “This is not some vague metabolic difference between
day and night. This is a tangible difference in the immune system that
influences sensitivity.”
The findings may well extend to the effects of other anti-cancer
drugs, as well as to radiation therapy and may provide a rationale for
adjusting the timing of chemotherapy to make it less toxic.
“There is one more very important clinical application of these
findings,” Antoch said, “as they provide a rationale for
developing drugs that can enhance the therapeutic index through the
modulation of the circadian clock. We have already started screening
sets of chemical compounds for their ability to affect this function.
We are also planning additional studies to discover the molecular
signals from the circadian machinery to the immune system that might
prove to be useful drug targets.”
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