Glowing mice help screen
cancer therapies
By Kristin Weidenbach
Mice that light up when
cancer cells are on the rampage and dim when the invaders
are poisoned by drugs may help researchers pinpoint
effective new anti-cancer drugs and will also spare the
lives of many lab mice.
A firefly gene makes the
promising technique possible. Scientists in the
laboratories of Christopher Contag, PhD, assistant
professor of pediatrics, and Robert Negrin, MD, associate
professor of medicine, have inserted the gene into human
tumor cells. When tumor cells are alive and healthy, the
firefly genes glow. The researchers then inject these
modified tumor cells into mice. Using an ultra-sensitive
video camera, the firefly light can be detected through a
mouse's skin and tissues, showing up on a computer screen
as colored blotches superimposed over the mouse's body.
Contag and Negrin tested
three standard chemotherapy drugs against human cervical
tumor cells to show that the new method is a reliable
predictor of the drugs' effectiveness. Their results are
reported in the October 12 issue of the Proceedings of
the National Academy of Sciences and in the October issue
of Neoplasia.
As the tumor invaded the
mouse's abdomen, the light emitted from the mouse became
more intense and spread over a greater area. Within days
of giving the mouse a chemotherapeutic drug, the
researchers could see the light diminish and recede,
indicating that the tumor cells were dying. More than two
months after the light had disappeared testing by an
alternative method confirmed that the mice remained free
from cancer.
Contag and Negrin believe
that the new technique will be especially useful for
testing drugs to treat minimal disease the small
number of cancer cells found early in disease or
following removal of a large tumor. Recent advances in
cancer diagnosis are allowing physicians to detect
minimal disease earlier and earlier, so drugs that can
rapidly kill these cells without further harming the
patient offer a better chance of fighting the disease.
Non-toxic alternatives
that will kill relatively small numbers of cancer cells
before they mass into a life-threatening tumor are
needed, said Contag. Drugs used to treat late stage
disease characterized by the presence of many rapidly
dividing cancer cells are usually very toxic, causing
unpleasant side-effects in the patient.
In addition to testing new
pharmaceuticals, the Stanford researchers are using the
firefly "glow gene" method to assess a new
anticancer therapy developed by Negrin. Immune system
cells called cytokine-induced killer (CIK) T cells
are collected from humans or mice, primed in the
laboratory, and returned to the body where they embark on
a search-and-destroy mission against tumor cells. The CIK
therapy successfully removed cancer cells in mice and is
now being tested, using human CIK cells, in a clinical
trial for lymphoma patients.
"We hope that the CIK
cells will destroy cancerous cells, such as malignant
cells lingering after a bone marrow transplant
procedure," said Negrin, who is associate director
of Stanford's Division of Bone Marrow Transplantation.
The researchers said they
are pleased that, in addition to potentially leading to
improvements in rapid drug screening, the glow gene
method will reduce the number of mice sacrificed in the
name of medical research. Neither the firefly gene nor
the ultra-sensitive camera harms the mouse. And because
the tumor cells can be seen through the animal's body,
there is no need to kill the mouse and dissect it to
ascertain what is happening within its tissues.
"You can follow one
group of mice over time, so you use fewer animals to get
more data more efficiently," said Contag.
"There is no other
method that can detect so few human cells
non-invasively," Negrin added.
Contag's group first
developed the glowing mouse in 1995 to follow the
progression of infectious diseases. He and his colleagues
injected Salmonella bacteria labeled with the
bioluminescent firefly gene into mice to see where they
settled in the mouse's gut and how the bacteria responded
to various antibiotics. The technology has since been
licensed to Xenogen, a company started by Contag and
others, including his wife, Pamela Reilly Contag, PhD,
who is president and CEO.
Co-authors of the current
study include researchers Thomas Sweeney, MD; Volker
Mailänder; Amanda Tucker; Adesuwa Olomu, MD; Weisheng
Zhang, PhD; and Yu-an Cao, PhD. Funding was provided by
the Public Health Service, the Leukemia Society of
America, the Medical Free Electron Laser Program, the
Mary L. Johnson Fund, the Hess Research Fund and The
Baxter Foundation. SR
|
