Joseph Takahashi researches the genetic and molecular basis of circadian rhythms and the body's "internal clocks."

ONOCOLOGISTS have long thought that cancer treatments tend to be more effective at certain times of the day. Now, researchers have discovered a molecular mechanism that explains this sensitivity. In experiments with mice, they found that the body's internal biological clock affects the survival of immune cells targeted by the anticancer drug cyclophosphamide (CY).

Initial experiments with normal mice, performed by Marina P. Antoch during her tenure in the lab of Joseph S. Takahashi, an HHMI investigator at Northwestern University, confirmed that animals treated with CY in late afternoon survived better than those whose treatments were initiated early in the morning. Antoch extended these original findings—by examining the mechanism for this difference—after she moved to Cleveland, Ohio, and established a research program in the department of cancer biology at the Cleveland Clinic's Lerner Research Institute.

Antoch and her colleagues used genetically altered mice that lacked specific components of the body's internal clock. "Defects in Clock or Bmal1 genes, which essentially damp the cycles of the internal clock," she reasoned, "may produce a 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."

The researchers discovered that Clock-mutant and Bmal1-knockout mice showed high sensitivity to CY at any time it was administered—as if it were always at optimal times of day. In contrast, the Cryptochrome-knockout mice showed more resistance to the drug at all times than did normal mice. When the Antoch team analyzed the knockout animals' immune-system B cells, they found that the presence or absence of functional Clock and Bmal1 genes determined their sensitivity to CY.

Photo: Matthew Gilson

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