Double Edge of Transplant Drugs

Malignant tumors in transplant patients are usually blamed on an immune system weakened by drugs. But a study in tomorrow's issue of Nature shows that the drugs may play a more direct role: A common immune suppressant can stimulate tumor cells to divide and spread. The finding suggests that it may be possible to design new drugs without this lethal side effect.

For nearly 20 years, doctors have used cyclosporine to dull the immune response, which would otherwise reject a transplant--a strategy that carries with it a 100-fold increase in tumor risk among these patients compared to healthy individuals. Recent experiments, however, have shown that cyclosporine can boost the body's production of TGF-b, a growth factor known to promote the spread of tumors.

To further explore cyclosporine's role in cancer, Minoru Hojo and his colleagues at the Tokyo University School of Medicine tested whether cyclosporine might help cancer cells become more mobile. They bathed a relatively benign strain of lung cancer cells in cyclosporine. Within 72 hours, the drugged cells began extending pseudopods--appendages that help a cell migrate. Another experiment showed that the treated cells were in fact getting around more easily.

When the researchers injected these tumor cells into the tail veins of 35 mice, nearly twice as many new tumors sprouted in the lungs of cyclosporine-treated mice compared to control animals. Exposed to cyclosporine, "the tumor cells become more malignant and more invasive," says Hojo. In both the petri dish and mouse experiments, cyclosporine's effects could be reversed by adding antibodies to TGF-b. To Hojo, this suggests that cyclosporine stimulates TGF-b production in transplant patients, which in turn spurs cancer cells.

The finding "throws a monkey wrench into our view of cyclosporine's mechanism" of tumor promotion, says Gary Nabel, a molecular biologist at the University of Michigan, Ann Arbor. It may also force people to rethink the role of the immune system in the cancer of transplant patients, he says. Hojo's group is now looking for ways to block TGF-b's tumor-promoting ability without curtailing its effectiveness at reining in the immune system during transplant operations.

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