Clocking Chemo's Effectiveness

The effectiveness of anticancer therapy depends partly on the time of day when it is administered; now, using knockout mouse models, researchers have shed new light on why this is.

Although clinicians first noticed this correlation between circadian timing and treatment success more than 30 years ago, is has seen limited application due to a lack of information about the underlying mechanisms. Researchers at the Cleveland Clinic Foundation (Cleveland, OH) and Northwestern University (Evanston, IL) report on the role of the major circadian transactivation complex, which regulates the expression of a number of genes that control circadian oscillation (Proc. Natl. Acad. Sci. USA, online 1 February, 10.1073/pnas.0409897102).

The research team treated mice with the common chemotherapeutic agent cyclophosphamide (CY) in the morning or in the late afternoon, and found that animals receiving CY early in the day were substantially more sensitive to its toxic effects. Using three mutant strains characterized by varying degrees of function of the CLOCK/BMAL1 complex, they then observed a direct correlation between the functional status of the major circadian transactivation complex and sensitivity to CY toxicity.

Understanding how time-of-day and allelic variations cause differences in reaction to chemotherapy should help doctors devise more effective and less toxic treatment schedules.

Mice Reveal Obesity-Diabetes Link

Scientists have discovered a molecular link between obesity and insulin resistance, providing new insights into the development and treatment of type 2 diabetes.

Based on previous clinical studies indicating that overweight people with insulin resistance have slightly elevated levels of NF-κB, Steven E. Shoelson and his colleagues at Joslin Diabetes Center and Harvard Medical School (Boston, MA) engineered mice to continuously produce low levels of this transcription factor in their livers. These mice, which were fed a normal diet, produced a number of proinflammatory cytokines at similar levels to mice on high fat diets, and exhibited high blood sugar, as well as hepatic and systemic insulin resistance (Nat. Med., February).

The team also found that salicylates, a class of anti-inflammatory drugs that includes aspirin, inhibited NF-κB action, suggesting a possible treatment for the growing numbers of people developing type 2 diabetes.

DNA Vaccine KOs TB in Mice

By combining standard therapy with an experimental DNA vaccine, a group of Korean researchers were able to cure mice of tuberculosis (TB) more quickly and effectively than with drugs alone.

TB, which is caused by Mycobacterium tuberculosis, kills more people than any other infectious disease; the emergence of drug-resistant strains and the AIDS epidemic have combined in recent years to further complicate the TB problem. Current treatments require patients to take drugs for up to a year; those that stop before completing the course are likely to succumb to the disease again—either by reactivation of the original infection or by reinfection.

Now, Youngchul Sung of Pohang University of Science and Technology (Republic of Korea) and his colleagues report successfully curing TB-infected mice with a combination of conventional drug therapy and a vaccine that contains two TB genes (Gene Therapy, online 3 February, 10.1038/sj.gt.3302465). All of the mice that received the vaccine and chemotherapy were disease-free 8 months after stopping treatment, compared to 40% in the drug-only group. These results suggest that a DNA vaccine, when combined with conventional therapy, may be a key to controlling the TB problem.