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Cell factories slow growth and shrink brain tumors
By Bijal P. Trivedi

American and Norwegian researchers are using gene therapy to fight an aggressive form of brain cancer by blocking the formation of blood vessels to the tumor. Cells containing the therapeutic gene are encased in a jelly-like substance, forming microscopic beads that are implanted near the tumor. Both teams report that these cellular bead implants are able to shrink tumors, some by up to 72 percent, and increase the life span of the animals. Although no brain tumor was completely eliminated, the authors of both reports propose that in the future this approach might be used in combination with radiation and chemotherapy to reduce the likelihood of recurrence.

Left: Endothelial cells form blood vessels. Right: Endostatin prevents blood vessel formation.

After removing a tumor, a neurosurgeon might implant these beads in the incision to shrink remaining tumors and discourage the growth of new ones, says Rona Carroll, of Harvard Medical School in Boston, who led the US research.

Both teams independently engineered cells that continuously secrete endostatin, a protein that inhibits the formation of blood vessels and starves the tumor of nutrients and oxygen. This, in turn, leads to the death of the cancerous tissue. The endostatin-secreting cells are encapsulated in a gel made from seaweed that permits the release of protein molecules but keeps the cells together in one place, like beach balls in a net.

The severity of brain cancer is related to the number of blood vessels that infiltrate the tumor; more vessels are characteristic of faster-growing aggressive tumors and an increasingly grim prognosis. Malignant brain cancers are particularly difficult to treat, and the average survival for a patient is about 12-18 months. Researchers believe that a continuous supply of endostatin close to the tumor could slow growth and the appearance of new tumors.

The two groups took slightly different approaches. Tracy-Ann Read and her colleagues at the University of Bergen, Norway, simultaneously implanted the endostatin-producing beads and tumor cells into the brains of rats. The treatment destroyed from 20 to 46 percent of the tumor in more than three-quarters of the animals. Regions surrounding the dead tumor tissue showed a more sparse network of smaller vessels.

In Read's study, all the untreated control animals died within 25 days. By contrast, half of the animals that received the endostatin survived up to 40 days and about one third were long-term survivors living more than 50 days.

Rona Carroll's team injected human brain tumors into mice and ten days later implanted the endostatin beads. Carroll found that the continuous exposure to endostatin reduced the tumors by 72 percent. The untreated control animals died within four weeks. Those with endostatin implants survived more than six months, and a few survived more than a year.

The reports are published in the January issue of Nature Biotechnology. Read's report suggests that beads could be tailored to specific cancer types by changing the genes carried by the encapsulated cells.

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Joki, T. et al. Continuous release of endostatin from microencapsulated engineered cells for tumor therapy. Nat Biotechnol 19, 35-39 (January 2001).
Read, T-A. et al. Local endostatin treatment of gliomas administered by microencapsulated producer cells. Nat Biotechnol 19, 29-34 (January 2001).

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