OncoLog, Volume 46, Number 11/12, November/December 2001 Page: 5
12 p. : ill.View a full description of this periodical.
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rs Target Different DNA Conformations
ions hip between Enigmatic Z-DNA and CancerI
4-1
_Iuent of Bioimmunotherapy, uses a rotary evaporator
used repeatedly in the preparation of a DNA-binding
colleagues who have participated in the development
Woodlands facility are Dr. Izabela Fokt (second
ioimmunotherap, and postdoctoral fellows (left to
mir Szymanski, and Szymon Kosinski.
ubicin that selectively binds Z-DNA (shown at right)
r anticancer agents. A complex of daunorubicin with
better, an enantiomeric pair of com-
pounds) are available that selectively
bind B-DNA and Z-DNA, further
therapeutic questions can be addressed.
Said Dr. Priebe, "So here we are hack at
the fundamental question, 'Can we design
small molecules that can target specific
sequences and forms of DNA and that
can control the expression of pathogenic
genes or other genes whose expression
it is important for us to control?"'
Before they developed WP900, Dr., -
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3
Priebe and his colleagues sought
to answer that question by creating
a method of developing small
molecules that bind targeted DNA
sequences, such as gene promoters,
with extremely high affinity and
sequence specificity. Their concept
involves identifying small molecu-
lar fragments of naturally occurring
DNA-binding agents or designing
small novel DNA-binding molecu-
lar fragments to create building
blocks (similar in concept to
interconnecting toy LEGO
blocks) that can be assembled to
produce new compounds with
much higher affinity and extended-
sequence specificity than any of
the parent compounds.
The first proof of this concept
was WP63 1, a six-base-pair-binding
agent that was synthesized by
linking several small subunits
of daunorubicin. When compared
with doxorubicin, an anticancer
agent similar to daunorubicin,
WP631 was more cytotoxic against
MCF-7 breast cancer cell lines.
A later in vitro transcription assay
showed that WP631 was very
effective at inhibiting transcription
from an adenovirus promoter
containing an Spi protein-binding
site, which the new compound
was designed to bind.
"So we can assemble these
'LEGO blocks' into DNA-binding
agents using structure-based
design and molecular modeling,"
explained Dr. Priebe, "or we can
use a combinatorial chemistry approach,
such that we create a library of random
DNA-binding agents and then identify
the agent with the highest affinity for
a desired sequence."
The combinatorial approach has
been used to identify another new
DNA-binding compound with unique
anticancer properties, called WP760.
Dr. Priebe and his colleagues Izabela
Fokt, Ph.D., a research associate in
the Department of Bioimmunotherapy,Teresa Przewloka, Ph.D., a postdoctoral
fellow, and others created a small library
of at least 80 randomly assembled
molecules that were recently sent to the
National Cancer Institute to be tested
for their activity against 60 different
disease-oriented cell lines. The results
showed that WP760 was selectively
cytotoxic against melanoma cell lines
and two non-small cell lung cancer
cell lines.
Libraries are also being created using
both the structure-based, rational design
method and the combinatorial chemistry
approach to identify molecules that
specifically control the transcription of
genes related to breast cancer. The first
structure-based design will target the
promoter of HER2/neu, a gene that is
commonly overexpressed in breast
cancers.
The hope of Dr. Priebe and his
colleagues is that these B-DNA-binding
compounds will be developed into small-
molecule therapeutic agents that will
treat cancer more effectively than do
some of the agents now available. And
the new "LEGO-block" strategy will also
make it easier to define the biological
importance of Z-DNA as well as identify
any involvement that Z-DNA has in the
development and progression of cancer.
The new strategy can also be used to
increase the base pair specificity of
WP900 and allow it to bind even
more tightly to its Z-DNA target.
"So for all practical reasons, this is
just the beginning of the story, which
could lead to the creation of new
anticancer agents using the molecular
LEGO concept and to the creation of a
new class of therapeutics based on the
targeting of Z-DNA," said Dr. Priebe.
"How practical it will be, no one can tell.
However, this approach opens new areas
of research that can be investigated in
more detail than ever before." "
FOR MORE INFORMATION, contact
Dr. Priebe at (281) 363-9072 or
(713) 792-3777 or by e-mail at
wpriebe@mdanderson.org.
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University of Texas M.D. Anderson Cancer Center. OncoLog, Volume 46, Number 11/12, November/December 2001, periodical, November 2001; Houston, Texas. (https://texashistory.unt.edu/ark:/67531/metapth903627/m1/9/: accessed July 18, 2024), University of North Texas Libraries, The Portal to Texas History, https://texashistory.unt.edu.; crediting UNT Libraries Government Documents Department.