March 3, 2005

Effective cancer treatments follow the internal clock

Joseph Takahashi leads a research team that seeks to explain the relationship between anti-cancer drugs and 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, a research team including Joseph S. Takahashi, a Howard Hughes Medical Institute investigator, has discovered a molecular mechanism that explains why sensitivity to anti-cancer drugs changes with the clock. The scientists said their findings, published online Feb. 1 by the Proceedings of the National Academy of Sciences (PNAS), could lead to new drug treatments that may be more effective because they harness the power and precision of the body’s internal clock.

“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 senior author Takahashi, who also is Walter and Mary Elizabeth Glass Professor in the Life  Sciences in Northwestern’s Weinberg College of Arts and Sciences.

In experiments, which were conducted in mice, the researchers found that the body’s internal biological clock affects the survival of immune cells that are targets of the anti-cancer drug cyclophosphamide (CY).

The initial experiments with normal mice, performed by Marina P. Antoch during her tenure in Takahashi’s lab at Northwestern, 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, a senior author on the PNAS paper, 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 a very different effect when compared to defects in the Cryptochrome genes, which, in contrast, ‘lock’ the circadian clock at the most active point in its cycle.”