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New drug delivery
system
DISGUISING a molecule to get it past the body’s immune system could
greatly
enhance the success of a
groundbreaking new therapy, Cancer Research
UK
scientists report in the British
Journal of Cancer1 this week.
In clinical trials, scientists are using a therapy known as ADEPT2 to
send
cancer-killing drugs directly to
tumours. But because the therapy uses an
enzyme3 not naturally found in
humans, a patient’s immune system can
recognise and reject the enzyme
before it can do its job.
Researchers in the Cancer Research UK Targeting and Imaging Group
disguised
a distinctive feature of the
enzyme to enable it to repeatedly elude the
immune system. The advance could
allow patients to safely receive multiple
courses of ADEPT to treat their
cancer.
ADEPT uses the ability of an enzyme to turn otherwise harmless
molecules, or
‘prodrugs’, into cell-killing
drugs.
The enzyme is given first and is designed to only attach to cancerous
cells.
When the prodrug is
given, it passes harmlessly through healthy tissue, but
in tumours is activated by the
enzyme and kills the cancer cells. Several
such combinations of enzyme and
prodrug are already being tested in clinical
trials.
ADEPT is a promising system for delivering therapy targeted to tumours,
but
is often hampered by immune
reactions to the enzyme.
The new research focussed on a bacterial enzyme, carboxypeptidase G2,
or CP, that is used in several ADEPT
combinations. Routinely, a molecular
‘tag’ was added to one end of
the enzyme as part of the production process.
But the tag itself reduced the
immune system’s response.
Lead author Dr Astrid Mayer, based at the Royal Free and
University
College
Medical
School
, says: “We were really surprised at the size of the effect.
Adding a molecular tag is common
practice in the laboratory, but is new for
products given to patients. In this
case it had a significant effect on the
immune response.
The tag masks a prominent feature of CP, hiding it from the immune
system.
Because the body can no
longer recognise that identifying feature, the
immune response to part of the
enzyme is reduced.
“We hope to find ways to disguise more features on the enzyme.
Minimising
the immune response to
carboxypeptidase will increase the potential of many
forms of ADEPT for clinical use.”
The immune system uses antibodies to recognise foreign
substances. Each antibody has a
highly specific shape that closely fits a
particular feature of a foreign
molecule, like a lock and key.
Upon the first exposure to an unknown substance, antibodies are made
that
fit its physical features. On
subsequent exposure the antibodies can lock
onto the matching features and call
in the body’s self-defences to destroy
the intruder.
Patients who received normal CP responded by producing antibodies to it
as
expected, indicating that the immune
system would reject further attempts to
use the treatment.
But patients who received the ‘tagged’ CP had significantly less
antibody in
their system, proving the success of
the disguise.
Professor Robert Souhami, Executive Director of Clinical and External
Affairs at Cancer Research
UK
, which owns the British Journal of Cancer,
says: “Novel cancer treatments
such as ADEPT use molecules that our immune
systems recognise as foreign. To be
fully effective against cancer cells,
these molecules first have to get
past the body’s own defences.
This study has identified a relatively simple method of
reducing the body’s
reaction against this enzyme.
Finding ways of disguising the molecular
features of certain cancer therapies
could make them safer and more
effective.”
1 British Journal of Cancer (2004) Vol 90 Issue 12
2 Antibody-directed
enzyme prodrug therapy
3 Enzymes are proteins
that catalyse chemical reactions in cells
----------------------------
SMOKING TURNS SALIVA
MALIGNANT
Cigarette smoke transforms healthy saliva into a deadly cocktail that
can
accelerate mouth cancer, according
to new research in the British Journal of
Cancer.
Normally, saliva provides a protective buffer between toxins and the
lining
of the mouth because it contains
important enzymes that fight and neutralise
harmful substances.
But the new research shows that the chemicals in tobacco smoke combine
with
saliva with devastating effect. They
destroy the protective components of
saliva - leaving a corrosive mix
that damages cells in the mouth and can
eventually turn them cancerous.
There are nearly 8,000 cases and 3,000 deaths from mouth cancer* in the
UK
every year - the main cause being
smoking. The researchers in this study
wanted to examine saliva¹s role in
the development of mouth cancer.
The study recreated the effects of cigarette smoke on cancerous cells of
the
mouth. Half of the cell samples were
exposed to cigarette smoke and the
other half to the saliva and
cigarette smoke mixture.
Cancerous cells were used in order to quickly assess whether the saliva
and
smoke mixture would speed the cancer¹s
development.
The study revealed that the longer the mouth cells were exposed to the
contaminated saliva, the more the
cells were damaged.
Dr Rafi Nagler, based at the Technion-Israel Institute of Technology,
who
co-led the study, says: "Most
people will find it very shocking that the
mixture of saliva and smoke is
actually more lethal to cells in the mouth
than cigarette smoke alone.
Our study shows that once exposed to cigarette smoke, our
normally healthy
saliva not only loses its beneficial
qualities but
actually aids in destroying the cells of the mouth and oral cavity.
Cigarette smoke is not only damaging
on its own, it can turn the body
against itself."
Saliva contains anti-oxidants. These are molecules that can help protect
the
body against cancer. The researchers
found that the cigarette smoke
destroyed them and turned saliva
into a dangerous cocktail of chemicals that
could accelerate the development of
mouth cancer.
Jean King, Director of Tobacco Control for Cancer Research
UK
, which owns
the British Journal of Cancer, says:
"It is World No Tobacco Day this week
and once more we see the dreadful
impact smoking can have on health. This
insight into how mouth cancer can
develop offers more reasons for smokers to
try and quit. People know of the
link with lung cancer, and this research
adds compelling evidence about the
damage smoking can do to the mouth."
Notes
*These figures refer to
cancers of the head and neck, which include nose,
mouth, lips, tongue, gums, tonsils,
pharynx and larynx cancer.
… Around 90 per cent of lung cancer cases are caused by tobacco
smoking and,
in addition, the 2002 IARC Working
Group concluded that tobacco smoking can
also cause cancers of the following
sites: upper aero-digestive tract (oral
cavity, nasal cavity, nasal sinuses,
pharynx, larynx and oesophagus),
pancreas, stomach, liver, lower
urinary tract (renal pelvis and bladder),
kidney, uterine cervix and myeloid
leukaemia.
… Mouth cancer can develop in any part of the mouth including the
tongue,
gums, lining of the mouth and lips.
The most important causes of mouth
cancer are smoking tobacco
(cigarettes, cigars and pipes), chewing tobacco
or betel quid with tobacco and
regularly drinking more than safe levels of
alcohol.
(2/6/04)
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