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volving several Italian research institutes has produced encouraging results.
The trial, conducted by the European Institute of Oncology, the National Cancer
Institute in Milan, and others found that
fenretinide
given by itself
reduced the incidence of
cancer in the
contralateral
breast by 40%
among premenopausal
women with a
history of the
disease. AnDr. Leslie Ford
other trial
combining fenretinide and tamoxifen is
ongoing.
JoAnne Zujewski, M.D., of NCI's
Medicine Branch, said she is using oral
tamoxifen and fenretinide in a pilot trial
to study tissue modification in 20 patients at increased risk for breast cancer,
with the idea that "it's unlikely any one
drug will be the answer."
Peter Ho, M.D., Ph.D., of NCI's Investigational Drug Branch, is conducting Phase I studies combining 9-cisretinoic acid with tamoxifen in patients
with advanced breast cancer.
Lavender
Other scientists are going farther
afield in the quest for breast cancer preventers, studying chemicals derived
from plants, including lavender.
The idea of using lavender to treat
cancer might not have surprised English
harvesters of centuries ago, who wore
sprigs under their hats to prevent sunstroke and headaches. As dubious as
that practice might be, the herb has a
long history of medicinal uses and is
still a focus of medical research.
1102 NEWS
Lavender is a source of perillyl alcohol, which when fed to rats in experiments at the University of
Wisconsin, Madison, prevented tumors from developing and caused
complete regression of advanced
mammary tumors.
Based on these early results, about
20 patients with a variety of advanced
cancers, including breast, ovarian, and
prostate, are enrolled in a phase I study
in which they take 20 to 30 capsules a
day, each containing 250 milligrams of
perillyl alcohol in soy oil. Because soy
products may also be anti-carcinogenic,
the question arises: Could the oil confound the study results?
"The oil is always a consideration," said Michael Gould, Ph.D., professor of human oncology at the
university. "If we found that it was
the oil that was causing an (anti-carcinogenic) effect, I'd be very happy.
It would be a very simple treatment.
And it would be less expensive than
perillyl alcohol."
Although this trial and planned
phase II studies both involve advanced cancer patients who are resistant to treatment, the intent is to
develop perillyl alcohol as a singleagent, primary treatment, Gould said.
Like tamoxifen, the substance will
also be investigated for its preventive
properties.
The agent blocks cell division, induces apoptosis, and in some cases induces differentiation, Gould said. Side
effects include nausea, but not severe
enough to prevent normal eating. The
only caution so far is against spicy
foods. "If you were on this for a long
period of time, you wouldn't want to
eat tacos every day," he said.
— Jan Ziegler
Scientists Figure
Out What Makes
HIV Stick
One of the enduring challenges in
AIDS research is figuring out exactly
how gpl20, the large, spike-like protein
on the surface of HIV, sticks to human
cells as the very first step in HIV infection. Solving this puzzle will have important implications for the future
design of drugs and vaccines to block
HIV from binding to cells.
In the mid-1980s, several studies implicated a short region of gpl20, called
C4, as the likely first point of contact
between HIV and its target, a protein receptor known as CD4 that sits on the
surface of human cells. But subsequent
studies yielded mixed results, leaving
scientists awash in questions about
whether C4 was really the sole binding
site on gpl20.
Now a team of researchers at the
National Institutes of Health may
have the answer.Writing
recently in the
Journal of
Biological
Chemistry,
t h e N I H re
~
searchers report that they
were able to
create synDr. Frank Robey
thetic, threedimensional copies of C4 that in laboratory studies hook onto CD4-positi ve
cells and block the binding of gp 120 to
the receptor. This, they said, provides
strong evidence that C4 alone binds to
the CD4 receptor as the first step in
HIVinfection.
Journal of the National Cancer Institute, Vol. 88, No. 16, August 21, 1996
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Taking this finding one step further,
the NIH scientists said they also have discovered the precise part of C4 that recognizes CD4. They found that when twisted
into its 3-D structure, C4 contains a hydrophobic (water-resistant) surface that is
identical almost down to the last amino
acid in HTV-1, HTV-2, and the simian immunodeficiency virus (SIV).
According to Frank Robey, Ph.D.,
lead author of the paper and a physical
chemist at the National Institute for Dental Research, "the hydrophobic region
could be the common thread that explains
how HTV-1 and HTV-2, two genetically
divergent viruses, maintain the fundamental ability to anchor onto immune cells
and initiate HIV infection." He said the
conservation of the hydrophobic region is
all the more striking because most of the
amino acids that fall outside of the hydrophobic region vary in HTV-1 and HTV-2.
Robey and colleagues said the new
results offer AIDS researchers a more
coherent molecular picture of that first
step in HIV infection and could be useful in designing new drugs and vaccines
to fight the virus. "If we can block the
initial interaction between HIV and
cells, we can inhibit infection," said
Marjorie Robert-Guroff, Ph.D., a coauthor on the paper and a scientist at
the National Cancer Institute. 'Today's
results give us a better theoretical game
plan to go in and block that very first
step in the cascade of events that leads
to HIV infection and ultimately AIDS."
Although experts have responded favorably to the paper, they also have
mentioned the need to confirm the data
using other strategies. "This finding further refines the mechanisms of CD4gpl20 binding," noted Carl Diefenbach,
Ph.D., associate director of the Basic
Sciences Program in the Division of
AIDS at NIH's National Institute of Al-
lergy and Infectious Diseases. "Only
through crystallography studies of these
same proteins interacting will the importance of the work be defined."
Still, the finding brings exciting
news to AIDS researchers during a summer that has yielded other hot leads in
the study of HIV infection. Earlier this
summer, several AIDS researchers
made headlines when they reported that
The predicted similarities in helical C4
among HIV-1 (rounded amino acids) and HIV-2
(hexagonal amino acids) are shown above.
Shared amino adds are in violet
HFV anchors not only to CD4, but also
to other protein receptors sitting on the
cell surface called fusin and CC-CKR-5.
These coreceptors serve as gateways for
HTV to enter cells after the virus sticks
toCD4.
Until now, scientists have been stymied in studying C4 and its interactions
with cells, such as human T cells and
macrophages. Current techniques for determining protein structure have yet to
provide a detailed picture of the large
and complex gpl20, making it impossible to study its actual 3-D conformation.
Another strategy has been to churn
out laboratory-made copies of C4 as substitutes for the real thing. But the syn-
Journal of the National Cancer Institute, Vol. 88, No. 16, August 21, 1996
thetic peptides, numbering just 18 amino
acids in length, are too short to assume
the natural 3-D shape that they have in
gpl20. This means scientists have had
to study linear versions of C4 that don't
have the same chemical properties that
the actual 3-D peptide has in the body.
New Approach
To attack these problems, Robey and
colleagues spent over 10 years inventing
a new approach for probing the structure
of C4 and other HTV peptides. After
some trial and error, they succeeded in
developing a method of chemically linking peptides, like links in a chain, into a
repeating string of peptides called a peptomer. Once anchored within a peptomer, the scientists found the individual
peptides assumed a 3-D form.
In the case of C4, Robey and colleagues reported last year that the peptide likely twists into a helical structure
in solutions with acid levels comparable
to those in the human body. They also
found these amino acids equally separate, like oil and vinegar, into hydrophobic and hydrophilic surfaces.
Following up on this work and serving as the source of the recent paper,
Robey et al. conducted a series of experiments to test the binding ability of
the helical C4 to the human T-cell receptor CD4. Their experiments showed
that helical C4, but not the linear version, locks onto CD4 and blocks gpl20
from binding to the receptor.
Based on these results, Robey said
he and his colleagues are now using the
C4 peptomer as a research tool to help
them track the cascade of cellular
events that lead to HIV infection. He
added that AIDS vaccine studies using
the peptomer are also in the works.
— Bob Kuska
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