Gene mutation may predict side
effects from chemotherapy
SEATTLE -- June 30,
2001 (Cancer Digest) -- Cancer patients who carry a genetic mutation
that hampers their ability to process a common vitamin tend to
suffer more severe side effects of a particular type of chemotherapy,
say researchers.
This is the first study
of its kind to show the impact of this genetic variant on drug
response and could help physicians tailor treatment to certain
cancer patients to minimize the harmful effects of the chemotherapy.
Dr. Nelli Ulrich, who
led a research team from the Fred Hutchinson Cancer Research
Center and University of Washington, Seattle, reported their
findings in the July 1 issue of Blood. Ulrich, a genetic epidemiolgist
at the Hutchinson Center says the study marks a step toward genetics-based
treatment strategies opened up in part by the Human Genome project.
"We know that
every patient reacts somewhat differently to the drugs they're
given and, until recently, our ability to understand how a patient
will react has been very limited, based on characteristics like
age and body weight," Ulrich said in a prepared statement.
"Now, with our
increasing understanding of genetics, we can better predict how
patients will process a drug and thus provide the appropriate
dose for that patient. Ultimately this will allow us to tailor
our drug dosages to reduce toxicity, or side effects, and increase
effectiveness,"she says.
The researchers examined
the medical records of 220 bone-marrow transplant patients who
received methotrexate, an antifolate drug used as standard therapy
for preventing graft-vs-host disease, a common complication of
marrow transplantation.
In analyzing the patients'
stored DNA, Ulrich and colleagues found that those with the lowest
activity of a key folate-metabolizing enzyme (called methylenetetrahydrofolate
reductase, or MTHFR) suffered the severest side effects and treatment
complications.
Side effects of methotrexate
include mouth sores, called oral mucositis, and delayed recovery
of cells called platelets needed for blood clotting. Oral mucositis
is characterized by a painful inflammation of the tissues lining
the mouth, throat and gastrointestinal tract; delayed platelet
recovery can leave a patient vulnerable to bleeding and requires
expensive platelet transfusions.
Patients with two copies
of the MTHFR variant had less than half the rate of folate-enzyme
activity as compared to those with only one copy of the mutation,
resulting in a 36 percent increase in oral mucositis symptoms
and a 34 percent slower recovery of platelet counts.
"Oral mucositis
is one of the worst side effects of marrow transplantation from
the patient's perspective," said Ulrich an assistant professor
of epidemiology at the UW. "It interferes with their eating,
drinking, talking, and sometimes even breathing. It also increases
the risk of infection as well as the cost and duration of the
hospital stay."
In addition to preventing
graft-vs-host disease in marrow-transplant patients, methotrexate
is used to treat certain cancers and, in lower doses, immune
diseases such as rheumatoid arthritis. The drug works by temporarily
interfering with the body's use of folic acid, a nutrient needed
for cell growth.
Nearly half of all
Americans carry a genetic mutation that to some degree interferes
with their ability to process and use folate, a vitamin found
in fruits, grains, and dark green, leafy vegetables. Also available
in supplement form as folic acid, this important nutrient is
best known for its role in preventing birth defects in the brain
and nervous system.
People with sluggish
folate metabolism in general are at no greater risk for disease
than the rest of the population. However, when exposed to a poor
diet or certain drugs, these people can suffer significant negative
clinical consequences, particularly if they are among the approximately
10 percent of Americans born with the most limited ability to
process this nutrient.
Ulrich's theory as
to why patients with the gene mutation suffer more severe side
effects of antifolate chemotherapy, is due to an inadequate folate
supply necessary to produce nucleotides -- a key component of
the DNA-repair machinery. Patients with variations in the MTHFR
gene, in the future, may be candidates for more customized therapy,
from altered dosages to alternative drugs.
Ulrich next plans to
study the effects of this variant on graft-vs-host disease, as
well as the effects of other genetic alterations in folate metabolism.
"If these results
are confirmed by further research," Ulrich said, "then
testing people for this common genetic variant may become a cost-effective
strategy for customizing treatment based on a patient's unique
genetic makeup."
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