|
 AMD UPDATE
Up until very recently a patient with a diagnosis of age-related
macular degeneration (AMD) could look forward only to an untreatable
and irreversible decline of vision. With advent of verteporfin photodynamic
therapy (PDT), however, AMD has become a treatable condition and
the prospects of many affected individuals has greatly improved.
In this month’s focus on AMD, EuroTimes provides an update
on the latest research into the degenerative eye condition, including
the most recent data on the longer term efficacy of PDT, the effect
diet may have on AMD, and the promising results obtained with anti-angiogenic
agents in actually reversing the course of the disease.
Anti-angiogenesis therapy comes of age
By
Laszlo Dosa In Fort Lauderdale
Forty years ago, Lieutenant Judah Folkman, United States Navy Medical
Corps, was busy in a laboratory at the Naval Medical Center in Bethesda,
Maryland, looking for a substitute for whole blood that could be
stored aboard ships and be available for transfusion.
Four decades later, Judah Folkman, MD, who first proposed the idea
of therapies taking advantage of anti-angiogenic processes, gave
the keynote address at the annual meeting of the Association for
Research in Vision and Ophthalmology.
Dr. Folkman began his medical research as an undergraduate student
at Ohio State University where he co-authored a paper describing
a new method of hepatectomy for liver cancer. After receiving his
B.A. degree cum laude at age 20, he went on to Harvard Medical School
where he found time to build the first atrio-ventricular implantable
pacemaker.
The draft into the Navy may have interrupted his surgical training
at Massachusetts General Hospital but not his scientific work. In
the course of his research, Dr. Folkman and a colleague experimented
with implantable silicone rubber polymers for the sustained-release
of drugs. This controlled-release technology led to the development
of Norplant, a five-year contraceptive, which is today used around
the world.
Also while in Bethesda, the young doctor began growing tumours in
isolated perfused organs, an experiment that gave birth to the theory
of angiogenesis – a concept that came to explain and shed
light on the secret of the growth of cancer cells.
The theory of angiogenesis postulates that tumours must have blood
in order to grow. Like every organ in the body, the cancer cell
needs nourishment, which is delivered by the blood. Moreover, it
occurred to Dr. Folkman that the tumour must have a mechanism, which
builds a supply line for those nutrients- i.e. blood vessels. And
if that were true, then interrupting that mechanism, blocking new
blood vessel growth, would deprive the tumour of its nutrients and
starve the cancer cells to death.
It had taken years to develop and spell out these theories, let
alone find acceptance for them. Writing in the New England Journal
of Medicine in 1971, Dr. Folkman laid out the basics of angiogenesis:
1.
The blood vessels in a tumour were new, and the tumour had to recruit
them.
2. The tumour "recruited" the vessels by sending out some
factor, first called TAF, tumour angiogenesis factor.
3. These diffusible proteins would bring in the vessels.
4. If this process could be turned off, the tumours should stay
small.
Subsequent
research discovered the existence of two angiogenesis inhibitors,
endostatin and angiostatin, which interfere with the formation of
new blood vessels in the tumour, blocking the nutrient flow to the
cancerous tumour. Dr. Folkman’s laboratory produced the first
purified angiogenesis molecule, as well as the first angiogenesis
inhibitors. This work gave rise to the concept of angiogenic disease,
which remains the subject of aggressive research in laboratories
all over the world.
While he was postulating theories and working on their development,
Dr. Folkman’s academic and medical career continued apace.
He was appointed Professor of Surgery at Harvard Medical School
and Surgeon-in-Chief at Children's Hospital Medical Center in Boston.
Ultimately, though, he relinquished these positions because he wanted
to concentrate all his efforts on research.
As angiogenesis and its inhibitors took their place in the rapidly
growing store of knowledge about cancer, Dr. Folkman and colleagues
turned their attention to the role of angiogenesis in eye disease.
Conventional thinking held that the growth of new blood vessels
was a side effect of dying tumour cells. In one seminal experiment,
live tumour cells were placed in one eye of a rabbit, and dying
tumour cells in the other. Soon, blood vessels began to sprout in
the live cells only but not in the dying ones. This showed that
the cells must be alive in order to procure their private blood
supply.
Other research identified the molecules responsible for the excess
blood vessel growth, which is the cause of diabetic retinopathy
and, in a different fashion, of macular degeneration. Many normal
and abnormal growth processes are thought to be due to abnormal
endothelial cell growth and regression. In the eye alone, abnormal
endothelial cell growth controls about 20 diseases.
The development of angiogenesis inhibitors has brought encouraging
results. For example, at the Dana Farber Cancer Institute in Boston,
a 47-year-old woman with Von Hippel-Lindau disease, which causes
hemangioblastomas in the eye and brain, was treated with one of
the new drugs (SU5416, Sugen). The patient had already lost one
eye to the tumour and had since become legally blind in the other
eye. But treatment with the drug stopped the leaking of the tumour
vessels and caused her eyesight to return within four weeks.
"Another antiangiogenesis agent rhuFab V2 (Lucentis™,
Genentech) also inhibited blood vessel growth in 26% of 64 patients
with advanced macular degeneration. The improved vision permitted
patients to read down an eye chart at least three lines after three
months of therapy," Dr. Folkman told his ARVO audience.
And he noted that certain drugs were found to be angiogenesis inhibitors
after they were approved by the FDA for another use. For example,
Cox-2 inhibitors, designed to treat arthritis, have been found to
increase endostatin serum levels.
And the research continues, with clinical trials of angiogenesis
inhibitor therapies for eye diseases now underway in three continents.
Judah
Folkman, MD
Harvard Medical School
Boston, Massachusets, US
judahfolkman@tch.harvard.edu
Top
|
