Monday, April 03, 2006
Rx: Thalidomide and Cancer
Rock Brynner, 54, historian, writer, former road manager for The Band and for Bob Dylan and son of the late actor Yul Brynner, knows both sides of the story of the drug thalidomide. In 1998, after suffering for five years from a rare immune disorder, pyoderma gangrenosum, Rock Brynner took thalidomide and went into remission. With Dr. Trent Stephens, he wrote "Dark Remedy" a history of thalidomide. "I didn't write the book because I had taken thalidomide," Mr. Brynner said. He looks and sounds very much like his famous father. "I did it as a historian because this was a story that needed telling."
The story of thalidomide is not only worth telling, it has gotten substantially more exciting even since 2001 when the interview with Rock Brynner (RB) was reported in the New York Times by Claudia Dreifus (CD). The unique anti-inflammatory properties of thalidomide have been harnessed for treating diseases as varied as multiple sclerosis, arthritis, leprosy, a variety of cancers, AIDS, and many other chronic and debilitating illnesses such as p. gangrenosum that Mr. Rock Brynner (RB) suffers from. The story began in 1950’s. Since pathogens were considered to be the underlying cause of most human diseases, scientists were racing to find new antibiotics. At this time, an ex-Nazi officer, Heinrich Mückter became in-charge of the research program for the company Chemie Grünenthal, and working with Wilhelm Kunz, obtained what looked like a promising compound. Unfortunately, this new drug which they named thalidomide had no effect as an antibiotic, anti-histamine or anti-tumor agent in rats and mice, and in fact they could not find a large enough dose to kill the animals. A logical conclusion would have been that the drug has no effect. The investigators however concluded that the drug has no side effects. The question of course was what the drug could be used for. Because the structure resembled that of barbiturates, thalidomide was tried as a sleeping pill and was indeed found to be effective, eventually being sold in 46 European countries as the safest sedative.
Reassured by its safety record in animals, and because of its anti-emetic effects, pregnant women began to take thalidomide freely as a cure for morning sickness. This is when its catastrophic effects began to surface as infants were born with flipper-like limbs; hands and feet attached to the body without arms or legs, later known as thalidomiders.
RB: As a historian, I look at thalidomide in its context. The 1950's were a time of unquestioning infatuation with science. Science and technology had defeated the fascist threat. In the cold war, science was seen as protecting our lives. The thalidomide scandal exposed us for the first time to the idea that powerful medicines can destroy lives and deform babies. Before that, medical folklore held that nothing injurious could cross the placenta.
As many as 20% adults taking thalidomide began to experience tingling and burning in fingers and toes with signs of nerve damage. Tragically, 40,000 individuals suffered from peripheral neuritis, and 12,000 infants were deformed by thalidomide, 5000 surviving past childhood, before the drug was finally with-drawn. It was later shown that the reason animal studies did not manifest any side effects was because thalidomide is not absorbed in rats and mice. Thanks to the heroic stance taken by Dr. Frances Kelsey at the FDA, thalidomide was never approved for use in the US, a stance for which she eventually won the President’s Award for Distinguished Federal Civilian Service in 1962.
CD: Why did you take thalidomide?
RB: I was fighting for my life, as almost everyone who comes to thalidomide is. Everything else paled beside that. In the film version of Dostoyevsky's ''Brothers Karamazov,'' Dmitri Karamazov wakes a pawnbroker, who says to him, ''It's late.'' To which Dmitri answers, ''For one who comes to a pawnbroker, it is always late.'' Well, I was at the pawnbroker's, and it was late. For five years, I had battled a mysterious, rare disease, pyoderma gangrenosum, where huge wounds on my legs kept growing larger and wouldn't heal. I had taken, at different times, cortisone, methotrexate, cyclosporine; none worked for long. My immune system was tearing up my skin anywhere I had a wound. Thinking practically, I was planning to end my life because, if we couldn't stop this, all my skin would be eaten away. Then my dermatologist mentioned anecdotal reports from Europe that thalidomide had been effective with pyoderma. I went to the medical library and read all I could. The rationale made sense: I had this autoimmune condition, in which one immune element, T.N.F.-alpha, was running amok in me for reasons unknown. Thalidomide represses that T.N.F.-alpha response. Fortunately, thalidomide did work for me.
In 1964, Dr. Jacob Sheskin, a Lithuanian Jew, was working with lepers in Jerusalem when he saw an extremely debilitated patient suffering from erythema nodosum leprosum (ENL) type of leprosy, who had been unable to sleep due to severe pain. Dr. Sheskin found an old bottle of thalidomide in his medicine cabinet, and gave two tablets to the patient who then slept better than he had in months. After another two tablets the following night, his lesions began to heal and it is to Dr. Sheskin’s credit that he made the association between the patient’s dramatic improvement and thalidomide. He had to contact Muckter to obtain thalidomide for a larger study. Eventually, the World Health Organization (WHO) confirmed a total remission of the disease in 99% of thousands of lepers treated in 52 countries. This is how and why, despite the sickening medical catastrophe associated with thalidomide, this drug never disappeared completely and was approved for the treatment of ENL in the USA by the FDA in 1998.
CD. A personal question. You are the son of Yul Brynner. As I was reading your book, I wondered if it was difficult to form an identity that was clearly your own.
RB. Well, I've had a separate identity for some time now. At one time or another I've written and starred in a one-man show on Broadway, earned an M.A. in philosophy and a Ph.D. in history, was bodyguard to Muhammad Ali, road manager for The Band and Bob Dylan and computer programmer for Bank of America. I've also written six books. My latest, about the subjective experience of time, is going out to a handful of publishers next month. These interests were all driven by my voracious curiosity more than a search for identity. Yes, it's difficult for the children of iconic figures to establish independent identities. But with all the suffering in this world, I wouldn't shed too many tears for those who had privileged youths. I had wonderful parents, especially through childhood. Later on, they both went a little crazy at times.
Thalidomide has now been tried in more than 130 human diseases, and at least 30 different mechanisms of action have been ascribed to the drug. Yet, the precise manner in which it exerts its anti-neoplastic effect remains unknown. In 1991, Dr. Gilla Kaplan of Rockefeller University in New York showed that TNF levels were very high in the blood and lesions of leprosy patients and that thalidomide reduced these levels by as much as 70%. In addition, Dr. Judah Folkman at Harvard Medical School showed that thalidomide can arrest the formation of new blood vessels by shutting off some necessary growth factors. The teratogenic effects on the fetus, which can occur following the ingestion of a single tablet of thalidomide at the wrong time (a 7-10 day window during the first trimester of pregnancy), turn out to be because thalidomide can stop the formation of new blood vessels or neo-angiogenesis. Finally, the drug also has a variety of effects on the immune system.
I have written previously about how cancer cells alter their microenvironment in such a way that it supports their growth at the expense of that of their normal counterparts. Such alterations may involve angiogenesis, production of TNF and abnormalities of immune regulatory cells, some of which are also the source of TNF. Thalidomide is a drug that is capable of affecting all three of these abnormalities in the malignant microenvironment, as well as having an effect on the cancer cells directly. True to form however, the introduction of thalidomide into cancer therapy did not happen as a result of logical planning, but rather dramatically as the result of one woman’s persistence. The wife of a 35 year old patient suffering from multiple myeloma, a hematologic malignancy with evidence of increased blood vessels in the bone marrow, was frantically searching for ways to save her husband. During her research, she came across Dr. Folkman who advised her to try thalidomide. She convinced her husband’s oncologists in Little Rock to do so. Although the patient himself did not benefit from the drug due to the advanced stage of his disease, several other patients treated subsequently did.
At the same time, our group had been investigating another hematologic malignancy, the pre-leukemic disorders called myelodysplastic syndromes (MDS). We had demonstrated that the primary pathology underlying the low blood counts in this disease is an excessive death of bone marrow cells caused by high TNF levels. In addition, there is also evidence of marrow neo-angiogenesis in MDS. We hypothesized that thalidomide could be a useful agent in this disease, and in 1998, treated 83 MDS patients, and showed that a subset responded, the majority of responders going from being heavily transfusion dependent to being transfusion independent.
CD: Do you think there will ever be a time when thalidomide stops being such a charged word?
RB: No. Because of its threat, everyone is working hard to keep the threat of thalidomide well known, especially Randy Warren, a Canadian thalidomide victim. He was the one who insisted that a picture of a deformed baby be on every package, that patients be obliged to watch a tape of a victim speaking and that the name never be changed or disguised with a euphemism. First and foremost, thalidomide deforms babies. Second, remarkably, it can save lives and diminish suffering. But everyone is working to eliminate thalidomide. As long as it exists, there's a threat.
Thankfully, a safer substitute has now been developed. This drug called Revlimid, which is less toxic and more potent than the parent drug thalidomide, is proving to be highly beneficial to patients with MDS and multiple myeloma. Most importantly, there are no untoward effects on the growing embryo. In a surprising twist, MDS patients who have a specific abnormality affecting chromosome 5 appear to be specially responsive to Revlimid, and the drug has recently received FDA approval for use in this type of MDS. Maybe thalidomide can finally be retired forever. As Randy Warren said, "When that day comes, all those involved in the suffering can gather together for thalidomide’s funeral."
- Stephens T, Brynner R. Dark Remedy: The impact of thalidomide and its revival as a vital medicine. Perseus Publishing, Cambridge, MA. 2001.
- Raza A et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodyplastic syndromes. Blood 98(4):958-965, 2001.
- List AF et al: Hematologic and Cytogenetic (CTG) Response to Lenalidomide (CC-5013) in Patients with Transfusion-Dependent (TD) Myelodysplastic Syndrome (MDS) and Chromosome 5q31.1 Deletion: Results of the Multicenter MDS-003 Study. ASCO May 7, 2005
- Raza A et al: Lenalidomide (CC-5013; RevlimidTM)-Induced Red Blood Cell (RBC) Transfusion-Independence (TI) Responses in Low-/Int-1-Risk Patients with Myelodysplastic Syndromes (MDS): Results of the Multicenter MDS 002 Study. 8th International Symposium on Myelodysplastic Syndromes May 12-15, 2005 Nagasaki, Japan.
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