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Research News
        
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.”