B, New Gene Therapy,
May Make Radiation and Chemo
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.
March 30, 1999
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