UC Davis Researches Discover a Weakness in
Pancreatic Cancer Cells Can Cut Growth in Half
Average survival time today with pancreatic cancer is
just four-and-a-half months; chemotherapy can extend that up to six
months
Nov. 7, 2008 - What many consider the meanest and
toughest cancer around – pancreatic cancer – may have a weakness after
all. Researchers at UC Davis Cancer Center say they have discovered a
deficiency in the cells of the cancer that can be used reduce by half
the normally very rapid progress of the deadliest of cancers.
The study results indicate that pancreatic cancer
cells cannot produce the amino acid arginine, which plays an essential
role in cell division, immune function and hormone regulation.
By depleting arginine levels in cell cultures and
animal models, the team was able to significantly reduce pancreatic
cancer-cell proliferation, according to the report in the October issue
of the International Journal of Cancer.
"There have been few significant advances in 15
years of testing available chemotherapy to treat pancreatic cancer,"
said Richard Bold, chief of surgical oncology at UC Davis and senior
author of the study.
"The lack of progress is particularly frustrating
because most patients are diagnosed after the disease has spread to
other organs, eliminating surgery as an option. We have to turn back to
basic science to come up with new treatments."
Bold explained that average survival time for those
diagnosed with pancreatic cancer is just four-and-a-half months,
although chemotherapy can extend that prognosis up to six months.
"There is a dire need to find new options for these
patients. While our findings do not suggest a cure for pancreatic
cancer, they do promise a possible way to extend the life expectancies
of those diagnosed with it," Bold said.
Bold and his colleagues hypothesized that
pancreatic cancer cells lack the ability to produce arginine. In human
pancreatic tumors, they measured levels of an enzyme — argininosuccinate
synthetase — required to synthesize arginine.
About Pancreatic Cancer
The pancreas is a
gland behind your stomach and in front of your spine. It
produces juices that help break down food and hormones
that help control blood sugar levels. Cancer of the
pancreas is the fourth-leading cause of cancer death in
the U.S. Some risk factors for developing pancreatic
cancer include:
Pancreatic cancer is
hard to catch early. It doesn't cause symptoms right
away. When you do get symptoms, they are often vague or
you may not notice them.
They include
yellowing of the skin and eyes, pain in the abdomen and
back, weight loss and fatigue. Also, because the
pancreas is hidden behind other organs, health care
providers cannot see or feel the tumors during routine
exams.
Because it is often
found late and it spreads quickly, pancreatic cancer can
be hard to treat. Possible treatments include surgery,
radiation and chemotherapy.
The enzyme was not detected in 87 percent of the 47
tumor specimens examined, suggesting that the majority of pancreatic
cancers require arginine for cell growth because of an inability to
synthesize the amino acid.
The researchers then conducted further tests using
pancreatic cell lines that represent the varying levels of
argininosuccinate synthetase observed in human tumor specimens. Focusing
on the lines with lowest levels, the researchers depleted arginine
levels in cultures of pancreatic cell lines using arginine deiminase, an
enzyme isolated from a Mycoplasma bacteria.
The enzyme was modified by adding polyethylene
glycol chains to increase size and circulatory time.
The researchers found that exposing the pancreatic
cancer cell lines to the modified arginine deiminase enzyme inhibited
cancer-cell proliferation by 50 percent.
They then treated mice bearing pancreatic tumors
with the same compound and found an identical outcome: a 50 percent
reduction in tumor growth.
Unique Approach
According to Bold, the current study represents a
unique approach to cancer treatment in that it is one of the first to
identify a metabolic pathway that can be leveraged to interrupt cancer
growth.
"Instead of killing cells as with typical
chemotherapy, we instead removed one of the key building blocks that
cancer cells need to function," Bold said.
Metabolic interruptions like this one are also
being studied for their potential in treating cancers of the blood, such
as leukemia and lymphoma. In those cases, depleting the amino acid
asparagine may be used in slowing cancer-cell growth.
Bold and his colleagues are continuing their
laboratory work on the effects of arginine deprivation on pancreatic
cancer. They will next be looking for ways to increase pancreatic cell
sensitivity to arginine deprivation.
The researchers have also begun designing human
clinical trials in cooperation with the manufacturer of arginine
deiminase, Polaris Pharmaceuticals.
"We're looking at whether we can combine this
treatment with certain kinds of chemotherapy," Bold said. "This
additional research is needed to inform the clinical work and move it
forward more quickly. The better we understand this process, the more we
can use it in the fight against pancreatic cancer."
Background Information
Additional study authors included Tawnya Bowles,
Joseph Galante, Colin Parsons and Subbulakshmi Virudachalam of the UC
Davis Department of Surgery; and Randie Kim and Hsing-Jien Kung of the
UC Davis Department of Biochemistry and Molecular Medicine.
The study was funded by DesigneRxPharmacolgics of
Vacaville, Calif.
UC Davis Cancer Center is a National Cancer
Institute-designated cancer center that cares for 9,000 adults and
children each year from throughout the Central Valley and inland
Northern California. The mutli-displinary pancreatico-biliary disease
group focuses on diseases of the liver and pancreas. Specialists in
surgical oncology, gastrointestinal surgery, medical oncology,
interventional radiology, gastroenterology, radiology and radiation
oncology work together to define treatment plans for patients and
develop novel medications. For more information, visit
www.ucdmc.ucdavis.edu/cancer.
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Bold and his colleagues are continuing their
laboratory work on the effects of arginine deprivation on pancreatic
cancer. They will next be looking for ways to increase pancreatic cell
sensitivity to arginine deprivation.