DRUGS that combat cancer by blocking the blood supply to tumours are to be
tried out for the first time on people. Because they disrupt chemical signals
exclusive to tumours, they could have fewer side effects than conventional
anticancer drugs, which also attack healthy cells.
Experiments described this month in Cancer Research show that the new drugs
block angiogenesis鈥攖he formation of fresh blood vessels. Angiogenesis
enables tumours to acquire their own blood supply. But researchers have yet to
prove that the drugs can halt the spread of tumours in people. 鈥淚t鈥檚 a proof of
principle,鈥� says Peter Hirth, head of research at Sugen, the company in Redwood
City, California that is developing the drugs.
Hirth says Sugen has tested stronger versions of the drugs successfully in
mice with cancer, and will publish the results soon. 鈥淚t dramatically reduced
the spread of the cancer,鈥� he says. Human trials will follow within a year.
These will show whether the drugs can shrink or eradicate tumours, as well as
stopping them growing and spreading. If the drug simply keeps tumours in check,
patients may have to take regular doses for the rest of their lives
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Pea-sized tumours that can no longer sustain themselves without their own
blood supply secrete a chemical SOS signal called vascular endothelial growth
factor (VEGF). 鈥淚t says `give me oxygen, give me blood and give me food鈥�,鈥� says
Hirth.
VEGF molecules diffuse through tissue and attach to docking sites on
endothelial cells which line the walls of blood vessels. The docking sites are
called flk-1 tyrosine kinase receptors in mice and KDR tyrosine receptors in
humans.
When VEGF binds to the docking site, it sends a signal through the receptor
into the endothelial cell. 鈥淭his activates a cascade of signals that go down
into the nucleus and tell the cell to divide,鈥� explains Hirth. After that, the
original blood vessel punctures itself and sprouts new subsidiary vessels
towards the source of the VEGF. Eventually, the vessels connect to and nourish
the tumour.
In 1993, Axel Ullrich and Werner Risau, German biologists who helped to found
Sugen, discovered the flk-1 tyrosine kinase receptor in mice and showed that it
only occurs on endothelial cells.
Sugen began the hunt for drugs that could block the receptors and starve
tumours without disturbing normal body chemistry. Hirth says that although VEGF
is important for forming blood vessels in embryos, adults only need it for
functions such as wound healing. So, in theory, only tumours should suffer if
the VEGF signal is intercepted.
In Cancer Research, the researchers report experiments with five
molecules designed by Sugen to block the receptor. In one experiment, using
endothelial cells from the human umbilical vein, the researchers proved they can
block KDR, the human equivalent of the mouse flk-1 receptor. This is an
important breakthrough because all previous experiments were on animals.
The report also covers two experiments in animals. In one, the compounds
stopped blood vessels growing in the outer membrane of a chicken egg. In
unexposed eggs these vessels, which nourish the embryo, grew normally. In the
other experiment, the researchers inserted pellets of VEGF into the abdomens of
mice to send 鈥渇ake鈥� tumour signals to neighbouring blood vessels. Mice not
receiving drugs to block the VEGF signal developed abdominal rashes which
were caused by blood leaking from punctured vessels. Mice receiving some of the
compounds remained healthy, suggesting that the signal had been intercepted.
Judah Folkman, an angiogenesis researcher at the Boston Children鈥檚 Hospital
in Massachusetts, says the developments have great potential. For example, he
says, they could lead to treatments for cancer and other angiogenic diseases,
such as blindness caused by the growth of unwanted blood vessels in the eyes of
the elderly and people with diabetes.
鈥淭his group is taking a unique approach to developing angiogenesis inhibitors
that block the receptor for an angiogenic factor,鈥� says Folkman. His colleagues
discovered another important chemical controlling angiogenesis called
angiostatin (鈥淏loodless crusaders鈥�, 2 March, p 30).
Adrian Harris, head of the Imperial Cancer Research Fund鈥檚 molecular oncology
laboratories in Oxford and a specialist in the study of VEGF, says the results
are encouraging but do not show whether injections of the drug will halt the
growth and spread of tumours in people. 鈥淐ritical experiments still remain to be
carried out,鈥� he says.
