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I-Kappa B, New Gene Therapy,
May Make Radiation and Chemo
More Effective

 March 30, 1999. University of North Carolina at Chapel Hill scientists have discovered they can shrink -- and in many cases eliminate -- human tumors grown in laboratory animals by shutting down a natural mechanism that prevents tumor cells from dying.
     Although not yet tried directly in humans, scientists believe their technique could one day significantly improve survival among patients with many kinds of cancer. They are planning the first human tests, which should begin later this year.
     The mechanism theyíve studied for more than three years involves NF-kappa B, a protein that attaches to DNA inside the nucleus of cells and turns genes on and off like a switch. When chemotherapy or radiation is used to kill cancer cells in a laboratory setting, these scientists reported two years ago, NF-kappa B kicks in and enables many cultured tumor cells to escape death. After developing resistance to the therapy, the cancer cells go on growing and spreading, and show no ill effects from the treatment.
     In the latest experiments, the scientists used a novel cancer gene therapy strategy to block NF-kappa B in mice with a natural inhibitor protein known as I-kappa B. Human tumors growing in the mice then became susceptible to chemotherapy, and in some cases disappeared altogether following treatment.
     A report on the discovery appears in the April issue of Nature Medicine, a scientific journal. Authors -- all affiliated with the UNC Lineberger Comprehensive Cancer Center -- are Dr. Cun-Yu Wang, a former graduate student and now clinical instructor in endodontics; Dr. James C. Cusack, assistant professor of surgery; laboratory technician Rong Liu; and Dr. Albert S. Baldwin Jr., associate professor of biology.
     "Our results are dramatic, and we believe they are going to be extraordinarily important for therapy of different kinds of cancer," said Baldwin, associate director of the Lineberger Center. "Although not everything that works in animals also works in humans, many times they do work. Because we think this is a mechanism that is important generally, and we now know how to counteract it, we are very optimistic."
     In the past, he said, no one has understood why many tumors donít respond to chemotherapy and radiation. NF-kappa B appears to be a front-line defense protecting both healthy cells and cancer cells from chemical attack.
     In the new experiments, researchers concentrated on human colorectal and fibrosarcoma tumors. They grew the tumors in mice and then treated them with a modified form of the inhibitor I-kappa B carried by a virus that could enter tumor cells. Treatment with a commonly-used chemotherapy compound known as CPT-11 was "eminently more successful," Baldwin said, when coupled with I-kappa B than when used by itself.
     Cusack, a surgical oncologist specializing in gene therapy, agreed that results so far were "very exciting." He and colleagues are now devising tumor models for other forms of cancer and expect to win U.S. Food and Drug Administration approval for a variety of clinical trials based on the new findings.
     "This forms the basis for developing a novel treatment strategy that is being explored further in preclinical studies and should be available to patients within the year," Cusack said. "These findings provide new insight into why many cancer cells frequently donít die when exposed to chemotherapy. The approach demonstrates a successful means of how we might overcome cancer cellsí defense mechanisms to make treatment more effective."
     He called the work a good example of the potential benefits of basic research that seeks to explain fundamental biology without preconceived notions and immediate applications.
     Support for the studies came from the National Cancer Institute, the American Cancer Society, the UNC Lineberger Comprehensive Cancer Center and the Leukemia Society of America.

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March 30, 1999