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    Gene therapy improves chemotherapy delivery

    Andrew M. Davidoff, MD

    Helping blood vessels that feed a tumor become mature and healthy at first might not seem like the best strategy for ridding a patient of cancer. But a team of St. Jude researchers using mouse models have discovered that a previously unknown anti-tumor action for the molecule interferon-beta (IFN-beta) does just that.

    The investigators demonstrated that IFN-beta sets up tumors to fail in two ways. First, the molecule stimulates production of a protein that helps the young blood vessels that initially grow in a slapdash manner become mature, which allows them to carry the chemotherapy drug topotecan into the tumor more effectively. IFN-beta also leaves the mature vasculature unable to continue expanding, thereby restricting the growth of the tumor, which depends on an expanding blood supply to grow.

    The new finding is significant because most drugs that remodel the immature vasculature in tumors work by inhibiting a protein called VEGF. Deprived of VEGF, inefficient new blood vessels die off, while the more efficient vessels survive for a brief period of time. In contrast, the current study showed that IFN-beta treatment causes young vessels to mature into healthy, efficient vessels that are maintained, thereby providing a longer window for improved chemotherapy delivery.

    In order to develop this treatment strategy, the team first had to figure out how to expose tumors to a sustained, therapeutic level of INF-beta, a protein with a very short half life, according to Andrew Davidoff, MD, director of surgical research, Surgery. Davidoff is senior author of a report on this work that appeared in the June issue of Molecular Cancer Research.

    “Interferon-beta has a half life in humans of only five minutes,” Davidoff said. “So either you have to keep administering the drug or give large quantities, which can cause serious side effects. We solved the problem with gene therapy.” Half-life is the amount of time it takes for half of the amount of drug in the body to disappear.

    Davidoff’s team used existing mouse models of human glioma and neuroblastoma that had been developed by injecting tumor cells into the animals. Gliomas are tumors that arise from glial, or nerve-supporting cells in the brain or spinal cord. Neuroblastoma is a type of solid tumor in children that arises from cells in the peripheral nervous system.

    They then inserted the gene for IFN-beta into a virus called AAV, and injected particles of that gene carrier into the mice after the tumors had grown. The AAV vector then homed in on liver cells, which used the gene to make and release IFN-beta into the bloodstream at a continuous level.

    Following injection of AAV carrying the IFN-beta gene, the blood supply of the tumors improved, while the vasculature of tumors in untreated animals remained highly twisted and disorganized. In addition, the blood vessels in tumors of animals treated with IFN-beta were covered with perivascular cells —cells that line and support normal blood vessels. These vessels were less permeable, and so did not release as much fluid into the tumor as did the abnormal blood vessels in animals that were not treated with IFNbeta, Davidoff noted. This prevented a buildup in fluid pressure outside the vasculature that would have prevented the immature vessels from delivering systemically (infused by a vein) administered topotecan to the tumors.

    The St. Jude researchers also discovered that IFN-beta works by stimulating production of a protein called angiopoietin-1 (Ang-1), which stimulates the changes in the vasculature. Ang-1 production began about four days after AAV IFN-B administration and reached a peak by day seven.

    “Our finding suggests that if this technique can be perfected for use in humans, we could significantly improve the anti-tumor activity of conventional chemotherapy drugs,” Davidoff said. “In the meantime, our technique will help us study the role of continuous delivery of IFN-beta in remodeling and maturation of blood vessels.”

    Other St. Jude authors of this study include Paxton Dickson, MD, and Christian Streck, MD, both of Surgery; Beth McCarville, MD, Radiological Sciences; Christopher Calabrese, PhD, and Richard Gilbertson, MD, PhD, both of Developmental Neurobiology; Clinton Stewart, PharmD, Pharmaceutical Sciences; Stephen Skapek, MD, Oncology; and former employees John Hamner and Catherine Ng.

    July 2007