In my research on how cancer avoids
detection and elimination by the immune system I came across an
interesting story of a potential treatment for cancer. This
treatment is especially interesting and prudent because the key to
the drugs effectiveness is the elimination of the 5th
hallmark of cancer, angiogenesis. The interesting part of the story
is that the drug was once the cause of terrible birth defects.
History:
In the late 1950s and early 1960s the
drug Thalidomide was used as a treatment for morning sickness in
pregnant women. Although never approved for sale by the FDA, many
pills were distributed for clinical trials; in other countries,
mostly European, the drug was certified and prescribed by doctors.
Very quickly doctors realized the connection between Thalidomide and
the rise in birth defects. The most common form of the defect was
phocomelia, the absence or shortening of the limbs. Fortunately,
thanks to the FDA's integrity, the spread of the drug was minimized
in the United States, sadly, the European countries suffered the
most, with over 10,000 recorded incidents.
For decades scientist struggled to
understand how the drug affected the development of limbs and it was
not until recently that true advances have been made. In 2006 Neil
Vargesson, a developmental biologist at the University of Aberdeen,
tested various purified metabolites (simpler forms of the enzymes
found in Thalidomide) on chicken embryos to determine which exactly
causes the deformity. The metabolite CPS49 was the only test to show
the deformity, additionally, almost immediately after being injected
into the embryo, developing blood vessels were destroyed. Using this
break through, Dr. Hiroshi Handa, of the Tokyo Institute of
Technology, prepared tests on zebrafish to determine what
developmental proteins were affected by CPS49. It was found that in
the presence of Thalidomide, the protein cereblon binds and
deactivates. Dr. Handa tinkered with the cereblon protein and made
changes in two places. These changes prevented Thalidomide from
binding and zebrafish embryos treated with Thalidomide developed
'relatively normal' fins (limbs). This was an important step because
it showed the drug could be tailored to be more effective against
cancer while removing some of the side effects.
Drug:
The hope is that this drug can be used
to stop the growth of blood vessels, and therefore starve the cancer
cells of nutrients. This treatment would be incredibly effective
against most types of cancer; however, this dream is a few years
away, as of now the FDA has approved Thalidomide to be used in
combination with dexamethasone to treat multiple myeloma. This
treatment has proven to be an effective form of chemotherapy.
Additionally Thalidomide has been shown to block a substance called
tumor necrosis factor (TNF). TNF stimulates the immune system to
attack harmful cells; however, over stimulation by TNF in cancer
patients leads to weight loss, fevers and night sweats. The
reduction of TNF by Thalidomide alleviates these symptoms.
Right now there are studies going on to progress the knowledge on how this drug effects the body. Dr. Handa's team continues to research cereblon's effect on the development of limbs and other researchers are working on the exact process that angiogenesis is halted. Once further research is done the drug can be refined and approved by the FDA. The on going clinical trials indicate that there is promise in combining Thalidomide with other drugs to effectively treat other types of cancer. The side effects of this treatment are still quite extensive, but with more research, hopefully this list will shorten enough to make the drug viable.
Resources:
http://www.mayoclinic.com/health/thalidomide/HQ01507
http://www.nytimes.com/2010/03/16/science/16limb.html?pagewanted=all
http://www.macmillan.org.uk/Cancerinformation/Cancertreatment/Treatmenttypes/Biologicaltherapies/Angiogenesisinhibitors/Thalidomide.aspx
http://www.medscape.com/viewarticle/434063
