New Task: Malaria drug might inhibit some cancers

In the 1970s and 1980s, researchers in Tanzania distributed millions of doses of chloroquine to children as part of a 5-year malaria-prevention project. While the study yielded only mixed results against that disease, the researchers noticed a striking drop in cases of Burkitt’s lymphoma, a blood cancer.

New studies in mice show that chloroquine may indeed prevent Burkitt’s lymphoma and also a rare disease called ataxia telangiectasia that can lead to leukemia.

Burkitt’s lymphoma is a cancer of B lymphocytes. A hyperactive version of a gene called myc turns these white blood cells malignant. The downward spiral typically begins with DNA damage that is not properly repaired. That leads to movement of DNA sections, including the myc gene, to unfamiliar locations on a chromosome, which can result in myc overactivation.

The protein that myc encodes, when superabundant, incites B lymphocytes to replicate out of control, Michael B. Kastan, a pediatric oncologist at St. Jude Children’s Research Hospital in Memphis, Tenn., and his colleagues report in the January Journal of Clinical Investigation.

Spurred by myc proteins, proliferating cells maintain a nutrient supply by hijacking a natural cell-housekeeping process called autophagy, in which cells chop up and dispose of damaged or obsolete cell components such as proteins. Autophagy also comes in handy during famine or other stressful times, recycling processed compounds as nutrients to keep the cell going.

Burkitt’s lymphoma cells, which have voracious appetites, commandeer the process to accommodate their growth needs, says Kastan.

Enter chloroquine, which targets cancerous cells that make excess myc protein and stalls autophagy in those cells. In experiments on mice with a hyperactive myc gene—a model of Burkitt’s lymphoma—animals given chloroquine survived 265 days on average, while mice without it lived 98 days.

A precancerous sign of Burkitt’s lymphoma is a soaring white blood cell count. Kastan and his team found that just three doses of chloroquine normalized such counts that were starting to rise in young mice.

However, mice allowed to develop full-blown lymphoma before receiving chloroquine didn’t benefit from the drug. The scientists found that chloroquine works only in the presence of a functional tumor-suppressing protein called p53. Established tumors can get the upper hand on p53 and silence the gene that encodes it.

Taken together, the findings suggest how mass distribution of chloroquine in Tanzania may have prevented many Burkitt’s lymphoma cases, Kastan and his team conclude.

But the p53 findings raise doubts that the drug will help against established cases, says Glen Brubaker, a public health physician at IMA World Health, based in New Windsor, Md. Brubaker, who coauthored the original Tanzania study, says the new report is surprising nevertheless. “Maybe we missed the direct effect of chloroquine.”

Since the myc gene has been implicated in at least 40 percent of cancers, several groups are now investigating chloroquine’s effect on various malignancies.

The new findings suggest that chloroquine might prevent cancer in people with premalignant or genetic conditions that predispose them to cancer, says Chi V. Dang, a hematology oncologist at the Johns Hopkins School of Medicine in Baltimore. Also, cancer patients who have undergone surgery to remove a tumor often remain at risk of recurrence, and chloroquine might benefit them, he speculates. “It’s a thing of beauty to discover new applications for old drugs,” Dang says.

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