A similar warning came out last week in the FT:
THURSDAY MAY 14 1998ÿÿInside Trackÿ
CANCER RESEARCH: New weapons
Clive Cookson looks at a wave of drugs that attempt to starve tumours by cutting off their blood supply
Medical researchers are tackling cancer in many different ways. The estimated 300 experimental cancer drugs and treatments in development range from orthodox chemotherapy to biotechnology approaches such as antibodies and gene therapy.
The latest technique to come under the media spotlight is to cut off the growing tumour's blood supply - an approach known scientifically as anti-angiogenesis.
A tumour is seen traditionally as a mass of malignant cells growing out of control, and conventional treatments attack these cells directly: removing them through surgery and/or poisoning them in situ through drugs (chemotherapy) or radiation (radiotherapy).
In contrast, the new wave of drugs designed to inhibit angiogenesis work indirectly, by cutting off the network of small blood vessels that deliver the oxygen and nutrients required by cells to proliferate.
More than a dozen different anti-angiogenic drugs are in development. Best known at the moment is a combination of two proteins, angiostatin and endostatin, being developed by EntreMed, a small US biotech company. An over-enthusiastic article about this in the New York Times led to a worldwide wave of publicity that propelled EntreMed's share price from $12 to a peak of $85 before it fell back to $32, as investors realised that the hype had been excessive.
Other companies testing drugs that work in a similar way include British Biotech, Chiro-science, Sugen, Oxigene, Agouron, Magainin, Genentech, Ribozyme, Abbott and Takeda.
The father of anti-angiogenesis is Judah Folkman at Boston Children's Hospital. In the 1970s he came up with the idea that tumours need to induce the growth of blood vessels to obtain sufficient nourishment. His laboratory discovered the angiostatin-endostatin combination during the early 1990s and he is still a leading researcher in the field.
Although the mechanism by which these compounds prevent angiogenesis is not known, their effect can be dramatic, at least in laboratory animals. They have made substantial tumours disappear entirely in mice - but the history of medical research is littered with would-be wonder drugs that cured cancer in mice but turned out to be ineffective or to have unacceptable side-effects in people. None of the proposed anti-angiogenic drugs is yet close to the end of clinical trials.
The most potent anti-angiogenic agents have been dis covered by following up a long-standing observation of cancer surgeons: when a primary tumour is removed, the operation often appears to stimulate the growth of secondary metastatic tumours elsewhere in the body. Dr Folkman and his colleagues reasoned that the main tumour was secreting biochemicals that prevented the secondaries developing - and they isolated a range of compounds that achieved this effect by starving distant tumours of blood supplies.
Judging by animal tests, the angiostatin-endostatin cocktail may be the fastest acting agent but it will not be ready to test on people before the end of this year. Others are further advanced in development:
Matrix metalloproteinase (MMP) inhibitors block enzymes secreted by cancer cells, which help blood vessels to spread by breaking down the surrounding tissues. The most advanced in clinical trials is Marimastat, the oral cancer drug on which the future of British Biotech depends. Agouron and Chiroscience are developing different MMP inhibitors.
Combretastatin, a synthetic derivative of a natural product extracted from the African bush willow, is about to start clinical trials under the auspices of Oxigene.
Inhibitors of vascular epithelial growth factor (VEGF), a natural protein that stimulates the formation of blood vessels, are being tested by Genentech and Ribozyme. The former is using an antibody for the purpose, the latter a synthetic chemical.
Thalidomide, the notorious drug withdrawn in the early 1960s after it caused birth defects in children, turns out to be a powerful anti-angiogenic agent (indeed this effect may explain the way it damages the developing foetus). EntreMed is testing thalidomide as a cancer drug.
Squalamine, an inhibitor of angiogenesis extracted from the dogfish shark, is beginning clinical trials in cancer patients. It is the first of a new class of natural molecules being developed by Magainin.
SU5416, which blocks the enzyme tyrosine kinase, is being tested as an anti-angiogenic drug for cancer by Sugen.
Details of these various drug candidates may not be of great interest to non-specialists. The point is to show the wide range of molecules being tested for their ability to starve tumours of their blood supply.
Although many of them will not make the grade in the clinic, even cautious oncologists expect a few anti-angiogenic drugs to work well on people. They will then add to our growing armory of cancer treatments, in combination with other approaches. But none will come close to curing cancer on its own. |
