Tamoxifen
Other known alias:
Nolvadex, Istubal, Valodex, ICI 46,474
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On June 25, 2013 the Scottish Parliament announced that Tamoxifen will now be available for women at high-risk of developing breast cancer1.
So what is Tamoxifen and how does it reduce the risk of developing breast cancer?
First off, Tamoxifen (or initially called ICI 46,474) is a fairly old drug which has been around since the 1960’s when Dr. Dora Richardson of ICI Pharmaceuticals (now AstraZeneca) first chemically synthesized it and Dr. Arthur Walpole pushed for its continued development. Being such an old drug has allowed it to develop quite the colourful past and highlights the importance of “looking outside the box” when developing new drug treatments.
When it was designed and created, scientists were busy trying to produce an anti-estrogen compound (something that could block the function of estrogen). They intended to use this drug as a Morning-after pill. However, in a glaring example of how success in animals does not always translate into success for humans…the drug worked as intended in rats but failed to prevent pregnancy in early human trials. In fact, it was later discovered to increase the fertility of human females by increasing ovulation! (This is why clinical trials are important to prove that a drug that works in animals actually works as intended in humans!)
To this day, Tamoxifen is still being actively researched and considered a potential drug for use to treat women who have problems with ovulation termed anovulation or Polycystic ovary syndrome2. How it actually works to promote increased ovulation is still not really understood. Looking at the scientific literature, there seems to be evidence that Tamoxifen can interact with both the ovaries and pituitary gland, thereby playing around with hormonal levels to increase the development of mature eggs and their release per cycle. This research is still ongoing even after 50 years of development! This is because the medical community and ICI Pharmaceuticals moved on with the development of Tamoxifen and began looking at other indications where blocking estrogen could be a benefit.
Breast Cancer
As with all cancers, the developing tumours take on some characteristics of the bodily tissue/organ that gave rise to the tumour. This is why certain cancer drugs can only be used to treat specific cancers originating from specific tissues of the body. In the case of breast cancer, the presence of estrogen receptors would be expected since the originating tissue would normally respond to estrogen (unless medical tests reveal the cancer is estrogen receptor negative).
Estrogen is a hormone, and like all hormones act as messengers that travel throughout the body to deliver its instructions. For breast tissue, estrogen, which is mainly released from the ovaries, signals the development and maintains the health of breasts. However, in the case of breast cancer, the estrogen normally found in the body can act as a signal to the tumour cells to divide and grow. Finding a way to block the ability of estrogen to send this signal could, in theory, block a growth signal in the tumours.
Enter Tamoxifen! Originally created to block estrogen in the hopes of preventing pregnancy, doctors have been using it for over 20 years to prevent breast cancer cells from growing. Tamoxifen mimics the shape of estrogen and binds those same estrogen receptors found inside breast cells, but unlike normal estrogen it does not send a signal to the cell to divide; kind of like a key that fits into a lock but cannot turn the lock to unlock it, while still preventing the real key from unlocking the lock!
Image was taken from: http://www.cancer.gov/cancertopics/understandingcancer/estrogenreceptors/AllPages
Unlike other cancer drugs, Tamoxifen does not kill the cancer cells, which is why it is termed oncostatic (“onco” meaning cancer, “static” meaning standing still) and not oncolytic (“onco” meaning cancer, “lytic” meaning to lyse, blow up or kill cells – like Lysol which kills bacteria) like other common anti-cancer drugs.
For cancer prevention in high risk populations, like the aforementioned Scottish population, Tamoxifen is designed to prevent any young cancer cells from receiving estrogen growth signals and becoming a tumour. People deemed to be “high-risk” often have a long family history of breast cancer and often through genetic testing have revealed indications that they will develop breast cancer within their lifetime. Tamoxifen, in these cases, would hopefully holds all those young, almost cancer cells, static and prevents them from growing and forming a tumour.
Consequences and benefits
As you may be aware up to this point, the risks of using Tamoxifen are related to preventing estrogen from performing its regular activities. People on Tamoxifen often suffer from hot flashes and other menopausal-like symptoms! Also, the use of Tamoxifen during pregnancy is not recommended by many scientists and doctors. Pregnancy normally results in large changes to the hormonal balance within a woman’s body, all of which are perfectly designed to ensure the promotion of a healthy uterus and ultimately the safety of the developing fetus. Messing around with an important hormone like estrogen can have consequences during the pregnancy. And this is proven by many clinical studies where pregnant women currently receiving Tamoxifen to control their cancers had a greater chance of having a baby with birth defects3!
I realize the irony of this since I already mentioned how Tamoxifen increases the fertility of women! Here we have one drug that can prevent the growth of cancers but can promote pregnancy in anovulating women!
To answer this paradox we must keep in mind the difference in these cases and the timeframe where Tamoxifen is prescribed. For women with difficulty ovulating, Tamoxifen was given at the start of their cycles for only 5 days, by the time of conception Tamoxifen would be eliminated from their bodies and the normal pregnancy timeline can continue without interruption. Compare this to the cases where Tamoxifen led to an increased chance of birth defects, the drug was present throughout pregnancy in an effort to protect the woman from breast cancer. Clearly, the presence of an estrogen blocking drug during pregnancy would not be advised.
Another glaring consequence of Tamoxifen relates to the fact that it does not kill breast cancer cells, only stops them from growing. It is theoretically possible that over time, the cancer cells can develop mutations that allow them to grow without the need of estrogen – thereby becoming resistant to Tamoxifen. This is why doctors may prescribe a variety of drugs in a “cocktail” to prevent the cancer from developing a resistance to the drugs (If one drug can’t get it, the other will!).
In the end, Tamoxifen has been used successfully in many instances to control the growth of breast cancer and prevent breast cancer recurrence. Its presence and longevity in the marketplace even after going off patent protection speaks to its success as a cancer drug. And continued research may yet reveal other estrogen dependent diseases that can treated by blocking estrogen with Tamoxifen. Due to its success and a bright future, we may continue to see this drug for many years to come!
References
1) New drug that can half risk of breast cancer developing to be available to Scots women; Daily Record; June 25, 2013. (http://www.dailyrecord.co.uk/news/health/new-drug-can-half-risk-1990976)
2) Lakhbir Kaur Dhaliwal et al.; Tamoxifen: An alternative to clomiphene in women with polycystic ovary syndrome; J Hum Reprod Sci. 2011 May-Aug; 4(2): 76–79.
3) Geert Braems et al.; Use of Tamoxifen Before and During Pregnancy; Oncologist. 2011 November; 16(11): 1547–1551.
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