COVER
Medical Pike
Thalidomide: From Dangerous Sedative
to Anti-Cancer Drug
November 23, 1999 New York /PSA Rising/ -- In the late 1950's, thalidomide was readily available in Europe for use as a sedative. It was believed to be non-toxic and to have no overdose. In the UK, from 1957 on, doctors were authorized to prescribe it to pregnant women for morning sickness. In Germany it was sold over the counter. Trust in thalidomide turned to shock as women who had taken it gave birth. The drug's soothing name -- in Greek, thalia means bloom, cheer, happiness -- became branded with the tragic horror of birth defects. Ten thousand babies were born with undeveloped limbs.
Only 17 American children were affected, most of them born in military families stationed overseas. Thalidomide never became a threat in the USA because it arrived late and was met at the gate by the FDA.
In September 1961, Dr. Frances Kelsey had been working for the FDA for less than a month. She was chosen to evaluate this drug. She says her bosses probably gave it to her, a novice medical officer, thinking it was an easy one. She had 60 days to assess four volumes of evidence (a standard amount in those days -- today it would hundreds of volumes). A lot was in German but much of it was fluff. At the NIH hearings on thalidomide in 1997, Dr. Kelsey recalled that "Many of the studies in support of new drugs were written really more as promotions than as scientific studies."
Dr. Kelsey and her team (a chemist and a pharmacologist) examined tests applied in Europe to see if thalidomide was toxic when taken for any extended period. They decided these tests were inadequate. And they had other concerns, enough to reject the drug:
The data to submit safety was very sketchy and anecdotal. The claims were quite fulsome, you might say, almost. It was of course perfectly nontoxic. It lacked hangover effect. It was nonhabituating, or addicting, and so on. But one by one, these claims sort of were modified somewhat.
I was particularly -- and all of us were -- concerned about the fact that you seem to be able to give enormous amounts, both to animals and humans, without any effect of perhaps drowsiness or sedation.When thalidomide was resubmitted, Dr. Kelsey went on testing. In early 1962, breakthrough evidence arrived from Britain:
We were continually concerned about the lack of data on metabolism, excretion, absorption, and this curious lack of toxicity. Then, at the end of February -- the 23rd, I think it was, actually -- we picked up a number -- it was actually the December 30th number -- of the British Medical Journal, which contained Florence's article posing the question, did thalidomide cause peripheral neuritis?
....Now, what we didn't know, again, was the German company had been questioned about peripheral neuritis as early as the winter of December of 1959, before our application was even submitted. The same person that asked them about it this time gave a paper -- I believe it was in May of 1960 -- describing a number of cases of peripheral neuritis, some of which seemed pretty severe.
....But it's difficult to exaggerate how popular this drug was at this time. I think it was the third largest-selling drug in Europe. As I mentioned, it was considered so safe that it was over-the-counter in many areas.
We were concerned about the peripheral neuritis, even if the companies did not seem to be. We sought some outside consultations with neurologists "When the FDA refused to allow sale of thalidomide, they still did know that it was a teratogen, a cause of birth defects. They had the reports of neurotoxicity, which were disturbing enough. Not till months later did the other evidence come in.
By the 90's scientists had discovered how thalidomide causes birth defects. In order for the embryo to develop limbs and organs, a network of new-grown blood vessels maps a path. The process of new blood vessel growth is called angiogenesis. Thalidomide blocks this. This has led to hope that with proper precautions it can be used again as medicine, this time far more potently.
Thalidomide's power to block angiogenesis makes it of great interest as a drug for cancer. New blood vessel growth is a critical process in embryos, in wound healing and in diseases involving overgrowth of tissues, such as cancer. In cancer, angiogenesis nourishes the primary tumor, allowing it to grow beyond pinhead size, and also nourishes clusters of cancer cells allowing them to break away and spread to new sites, i.e. metastasize.
Are drugs that are powerful enough to stop blood vessel growth in adults tolerable, though, by people who have cancer? One thing to watch for as data comes out from clinical trials of thalidomide for cancer is how the drug's side effects impact expectations surrounding the two best known antiangiogenesis drugs, Angiostatin and Endostatin. Under an exclusive agreement with Dr. Judah Folkman of Children's Hospital in Boston, thalidomide as well as Angiostatin and Endostatin are being developed and testted by one company, EntreMed in Irvine, CA.
Thalidomide: Potential Benefits and Risk. An Open Public Scientific Workshop Sponsored by the National Institutes of Health and the Food and Drug Administration, September 9-10, 1997, Bethesda, MD.
Thalidomide Neuropathy National Institutes of Health (NIH) Thalidomide Meeting 9/9/97
The Neuropathy Trust: Peripheral Nerve, a Closer Look Supporting people affected by the neurological condition - PERIPHERAL NEUROPATHNCI's Division of Clinical Sciences Will Test Thalidomide in Patients with Advanced Colon Cancer August 6, 1999
Thalidomide Information, FDA Center for Drug Evaluation and Research, July 16 1998
EntreMed page on Antiangiogenesis drugs including thalidomide
These two negative findings turn up in the background literature -- clinical trials reults seem to invalidate them:
Thalidomide promotes metastasis of prostate adenocarcinoma cells (PA III) in L-W rats Pollard M, Cancer Lett 1996 Mar 19;101(1):21-4
Anticancer Res 1996 Nov-Dec;16(6B):3673-7 Failure of thalidomide to inhibit tumor growth and angiogenesis in vivo. Gutman M, Szold A, Ravid A, Lazauskas T, Merimsky O, Klausner JM Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv University, Israel.For links to some online cancer databases and journals see PCa Research page
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