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|  File Name      : LASECANC.ASC     |  Online Date     :  01/15/96          |
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                  UV Laser Light Used Against Viruses, Cancer

A chemist at Washington University in St. Louis literally has shone new light
on a potential way to treat viral diseases and cancer.  John-Stephen Taylor,
Ph.D., Washington University associate professor of chemistry in Arts and
Sciences, has created a modified piece of DNA that can be fragmented when
exposed to ultraviolet light by laser. Once broken into two pieces, the longer
piece of the modified DNA binds to a target site - a virus or cancer - and
makes the target dysfunctional. The breakthrough provides scientists new ways
to battle viruses and cancers and may change or even displace chemotherapy.

DNA is a double-stranded helix molecule; located in the nucleus of every human
cell, it contains cellular plans encoded in segments of DNA called genes.
Messenger RNA is a single-stranded molecule responsible for carrying out the
plans of DNA by directing the formation of proteins.  Potential therapeutic
uses for Taylor's building block are based on a strategy called antisense,
whereby matching genetic sequences bind to specific messenger RNA molecules,
inactivating their genetic message. Because the genetic instructions carr
ied by Taylor's photocleavable building blocks can only be activated to bind
in conjunction with light, the building block can be selectively activated in
an area containing a cancer, thereby leaving good cells alone. Conventional
chemotherapy, on the other hand, kills beneficial cells as well as cancer
cells.

Taylor incorporated the modified DNA piece, which he calls a photocleavable
subunit, into another short piece of DNA by automated DNA synthesis. When
light is shone on the DNA molecule bearing the photocleavable piece, the DNA
strand falls apart into a long and a short fragment. The sequence of the long
fragment is designed so that it matches a sequence in another DNA molecule to
which it now binds, changing its genetic message.

"We wanted to demonstrate how you can use such a photocleavable subunit to
trigger something biologically useful," Taylor says. "We demonstrated that we
could design a molecule that is otherwise incapable of binding to another DNA
molecule but in the presence of light will break apart into two fragments, one
of which is capable of binding to a matching sequence in a target DNA or RNA
molecule."

Taylor put the photocleavable subunit into a short piece of DNA, shone
ultraviolet light on it and, using gel electrophoresis, a process that
separates DNA fragments of differing sizes, watched the DNA break into the
large and small fragment. The target site for the larger DNA fragment was a
bacteriophage, a bacterial virus, of the often-used laboratory organism E.
coli. The laser used operates at 10 pulses per second, and it took 80 pulses,
or just 8 seconds, to cleave the DNA.

"We showed in the absence of light, there is no binding of the DNA to the
bacteriophage; with light, the DNA is cleaved and the shorter fragment
dissociates from the larger fragment, which can now bind to the
bacteriophage," Taylor says. "This is another tool that can be engineered into
a molecule. In this case, light is the switch to activate binding to genetic
material."

Taylor published his results in the November 1995 issue of the Journal of the
American Chemical Society. His research was supported by grants from the
National Institutes of Health.  Light already is used in a number of medical
therapies. For instance, dermatologists use a technique called photophoresis
for psoriasis and cancer treatments. And laser ablation burns away tissue in
various diseases, including cataracts. But the photocleavable building blocks
potentially offer a new dimension of precision to existing therapies and ones
in the works.

"Light is very useful biochemically," Taylor observes. "You can spatially
locate it, point it to a specific site and turn it on and off. The whole point
about light is it's a wonderful trigger because it can be literally turned on
and off with the flick of a switch. With most drugs, once they're ingested,
they go and react everywhere, with little control. Building in the
photocleavable unit provides the means to activate the molecule in a specific
location at a specific time."

One of Taylor's areas of expertise in synthetic organic chemistry is
ultraviolet light damage leading to skin cancer. Sponsored by the National
Cancer Institute, Taylor's work involves synthesizing genetic damage produced
by sunlight and then studying the photoproducts produced by the damage, the
processes of genetic mutations, and potential ways to reverse the damage or
prevent it.

In 1986, he and his team discovered the Dewar photoproduct, one of the chief
cancer-causing products resulting from UV damage that is implicated in the
beginning of skin cancer. In his skin cancer work, Taylor has created building
blocks for DNA photoproducts essentially to produce pure compounds to study
the cancer process.

His current work was sparked by an interest in understanding the DNA breaks
caused by ionizing radiation where a particle has enough energy to remove an
electron from an atom or molecule, and in the process produces an ion and a
free electron. More graphically, this kind of radiation is marked by breaking
both strands of the DNA helix molecule, allowing no chance for the DNA to
repair itself. While this is one of the most destructive features of ionizing
radiation, the double strand break also makes ionizing radiation a useful
therapeutic tool in cancer treatment, for instance.

Taylor's breakthrough makes it possible to use DNA strand cleavage to turn on
and/or off potentially useful antisense drugs.  "Our motivation for doing this
work was to see if we could generate the kinds of DNA breaks produced by
ionizing radiation and see if that destructive act can be used beneficially,"
Taylor says. "There is lots of interest in the basic questions of what kinds
of double-stranded DNA breaks are difficult or easy to repair and how are
these problems solved? This is an invention that has perhaps many different
uses. Certainly, it makes biochemists look at light in a different way."
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