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The Study
Previous studies by Shami, Brice Weinberg at Duke University and
colleagues showed nitric oxide inhibits growth and induces cell
suicide among acute myeloid leukemia cells grown in culture. In
the new study, the researchers tested compounds that would trigger
the release of nitric oxide inside cancer cells.
Shami and Wang tested in cell culture and sometimes in mice some
50 compounds designed to trigger nitric oxide release, and found
JS-K was the most active. The compounds were sent to them by the
researchers at NCI, where JS-K was synthesized by study coauthor
Joseph Saavedra. It is named for his initials and is letter K
in a series of compounds he synthesized. JS-K's chemical name
is O2-(2,4-Dinitrophenyl) 1-[4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate.
In a key experiment, acute myeloid leukemia cells known as HL-60
cells were implanted under the skin of mice that had suppressed
immune systems and could not naturally combat the cancer cells,
which grew to produce tumors. After 16 days of treatment with
JS-K, the volume of the tumors was less than half the tumor volume
in untreated mice. The treated mice did not suffer significant
low blood pressure.
When the AML cells were grown in culture flasks, three days of
treatment with JS-K caused the rate of cell suicide (called apoptosis)
to increase from 7 percent without treatment to 27 percent and
43 percent, respectively, with two different concentrations of
JS-K.
"This is in the league of currently available chemotherapeutic
agents for this and other cancers," Shami said.
He said further experiments might find some other compound that
works like JS-K but is more effective, more soluble or easier
to use, so JS-K is considered a "lead compound" for
further study and not necessarily a future chemotherapy drug.
How JS-K Works
JS-K is designed to react with natural enzymes called glutathione
S-transferases, or GSTs, which help pump foreign substances out
of certain cells. GSTs help the liver get rid of toxic substances
in blood. But they also help cancer cells resist chemotherapy
drugs. When GSTs in cancer cells interact with JS-K, there are
two anticancer effects: GST activity is inhibited, making the
cells less resistant to chemotherapy drugs, and nitric oxide is
released.
"You have delivered nitric oxide inside your target cancer
cell, and the nitric oxide will kill it," Shami said. "Other
cancer-killing mechanism also may be occurring, and more work
is needed to define them."
Much less GST is found in healthy cells compared with cancer cells,
so researchers hope the reaction of GST with JS-K to release nitric
oxide will occur to a much greater extent in cancer cells without
harming healthy cells.
Funding and Commercialization
The new study was funded by the National Cancer Institute, the
Leukemia & Lymphoma Society and the National Institute of
Environmental Health Sciences.
JS-K's potential has been recognized by the NCI. The institute
accepted the compound into its Rapid Access to Intervention Development
(RAID) program, which tries to speed development of new cancer
therapies. Work done so far within the RAID program has shown
JS-K is active against a broad spectrum of cancer cells.
"Dr. Shami is the first investigator in Utah to win a RAID
grant," says Eric Gosink, of the University of Utah's Technology
Transfer Office. "This grant allows him to coordinate work
with a panel of National Institutes of Health scientists dedicated
to testing the efficacy of the compound."
The Technology Transfer Office is trying to commercialize development
of the experimental cancer drug and is seeking patent protection
for its action as an anticancer compound, while the NCI is seeking
a patent on the entire family of compounds to which JS-K belongs,
Shami and Gosink said.
Acute Myeloid Leukemia
Acute myeloid or myelogenous leukemia (AML) is the most common
and most deadly form of leukemia, with 10,600 new cases diagnosed
in the United States in 2002, according to the Leukemia &
Lymphoma Society booklet Facts 2002. Only 19 percent of
patients overall - and 46 percent of childhood AML patients -
survive five years or more, the group says. That illustrates the
need for new drugs to treat AML.
In AML, bone marrow cells called myeloblasts become cancerous
instead of developing normally into white blood cells called neutrophils
and monocytes. The cancerous cells build up in the bone marrow,
which then fails to make enough normal blood cells, causing weakness,
shortness of breath, bleeding, fever, vulnerability to infection
and other symptoms. The cancerous cells can spread to other organs.
Death can come from infection or from bleeding due to lack of
adequate platelets.
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