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| LE Magazine October 1999
The FDA's recent approval of tamoxifen for the
reduction of the risk of breast cancer in high-risk healthy women prompted
us to take a closer look at the drug. What we discovered may surprise you.
Tamoxifen works by blocking estrogen, but blocking estrogen is not its
only, or in some cases, most important action. The anti-cancer effects of
tamoxifen are found in other substances that are far less toxic and just
as powerful. Stay with us-what you learn may save your life.
Estrogen and breast cancer Estrogen sends messages to cells through what are known as estrogen
receptors. Receptors are essentially "doors" on cells that allow entry of
substances like estrogen. In the case of estrogen, the "door" is very big,
and it will also allow molecules that resemble estrogen to enter as well.
This is why fake estrogens and estrogen blockers can provoke cells to
react. If the receptor was very small or very particular, it wouldn't
allow the fakes in.
Receptors are not like doors, however, in the sense that they're not
square. They're curvy-like a jigsaw puzzle. When a molecule of the right
shape comes along, it fits in the receptor and makes contact with points
just inside the receptor's "door jamb." Touching these contact points sets
off a series of chemical reactions that send a signal inside the cell.
One of the most important messages estrogen delivers is to grow-divide,
multiply. For this reason, estrogen is crucial in the development of the
fetus. For the same reason, it's usually found at the scene of breast
cancer, where it eggs on hormone-responsive cancer cells. It's estimated
that 50-70% of all breast cancers are estrogen receptor-positive-they grow
in the presence of estrogen. And according to Dr. Kent Osborne of Baylor
University, this figure could be much higher because of problems in the
classification system.
Successful communication between the messenger and the cell depends on
the messenger (estrogen) fitting the door (receptor) exactly so as to make
all the contact points. Estrogen produced naturally in the body fits
inside the estrogen receptor perfectly and sends certain predetermined
signals. Estrogen look-alikes such as tamoxifen fit in the door, but don't
make all the contacts because they're not exactly the right shape. As a
result, they send odd signals or block them altogether.
What's disturbing about these synthetic look-alikes is that scientists
don't know what signals they actually do send once they get into the
receptor. They know some of the signals. For example, they know that
tamoxifen blocks the "grow" signal in breast tissue. They know the same
molecule promotes the "grow" signal in uterine tissue. They know Premarin
sends a "grow" signal to bone. But what signals, for example, does the
estrogen mimicker/blocker, raloxifene, send to the brain through its
estrogen receptors? Nobody knows.
Secrets of tamoxifen
The most well-publicized aspect of tamoxifen's mode of action against
breast cancer is that it blocks estrogen. What's not usually appreciated
is that tamoxifen has other modes of action. The other actions are just as
important, or in some cases more important, than the estrogen-blocking
effect. And they are not unique to tamoxifen.
Tamoxifen also works in estrogen receptor-negative breast cancers and
progesterone receptor-positive breast cancers. This is because tamoxifen
not only blocks the estrogen "grow" signal, it blocks another type of
"grow" signal known as protein kinase C (PKC). PKC is another one of those
contact points inside the door jamb, and blocking this signal stops
oncogenes (cancer genes) from activating. PKC also controls cell growth
and transformation signals.
Tamoxifen promotes free radicals
A surprising study was published in the Journal of Biological
Chemistry in 1996. Using estrogen receptor-negative breast cancer
cells, researchers from the University of Southern California showed that
tamoxifen uses free radicals to inhibit PKC. How it generates the radicals
is not known. Researchers do know, however, that it takes very low doses
of tamoxifen to create this effect. Estrogen receptor-positive cancer
cells require much higher doses of tamoxifen. A very important finding of
this study is that antioxidant vitamins E, C and beta-carotene (but not
glutathione) kept tamoxifen from working in estrogen receptor-negative
cells. If confirmed in vivo, this could mean that women with
receptor-negative breast cancer taking tamoxifen should not take
antioxidants.
A group at Zeneca Pharmaceuticals, the manufacturer of tamoxifen, has
reported a similar phenomenon. In estrogen receptor-negative ovarian and
leukemia cells, tamoxifen depletes the body's natural antioxidants and
provokes free radicals. The radicals then cause the cancer cells to
self-destruct. An important caveat of both this and the above study is
that both have only been done in the test tube and only in estrogen
receptor-negative cancer cells.
Tamoxifen also stops free radicals
It's not surprising that tamoxifen generates free radicals since most,
if not all, chemotherapies do. However, it is surprising that tamoxifen is
also a powerful antioxidant. The antioxidant effect is found in its
metabolite, 4-hydroxytamoxifen.
Women who take tamoxifen for 6 months have far fewer free radicals in
their blood than before they took it. They also have higher levels of
antioxidant vitamins and enzymes, indicating that tamoxifen conserves the
body's own antioxidant defenses (except in the above studies in estrogen
receptor-negative cells).
Numerous studies show that 4-hydroxytamoxifen strongly inhibits
oxidative damage to a broad range of important substances-lipids, DNA and
protein. This ability to stop free radicals is part of its anti-cancer
effect. In studies on animals treated with the chemical TPA, tamoxifen was
effective at inhibiting free radicals so that not enough DNA damage
occurred to transform the cells.
Another aspect of tamoxifen's anti-cancer action is its ability to
interfere with the cell cycle. The cell cycle is a predetermined program a
cell goes through to make a new cell. Normal cells "put on the brakes" at
certain points during the process so that things can be checked for
accuracy. This ensures that abnormal cells don't get duplicated. However,
cancer cells "override" the brakes. They duplicate themselves at
break-neck speed with no checks on accuracy. Chemotherapy works by
"setting" the brakes. Tamoxifen is one of the chemotherapies that does
this.
What's wrong with tamoxifen
All this sounds great. Why not ake tamoxifen and be happy? Because
tamoxifen has severe drawbacks, some of which are just now coming to
light. While some studies show that tamoxifen works better at five years
than two, other research confirms that tamoxifen always "turns" on its
user in months or years, and begins feeding new, tamoxifen-dependent
cancer. A new chemical is being tested to combat this "problem." But the
new chemical may create problems of its own.
Meanwhile, there are hints that tamoxifen "resistance," as it's known,
is the result of permanent damage caused by the drug. One area that might
be damaged is tumor suppressor gene p53, a player in the process that
stops the cell cycle and makes sure cancer cells don't get replicated. In
the healthy person, p53 sends signals that stop the cell cycle when
abnormal cells are involved, and causes them to self-destruct. Using human
breast cancer cells, researchers in France showed that tamoxifen stops p53
from working. While this may sensitize cancer cells to the effects of
chemotherapy, the same phenomenon in a healthy person would cripple their
ability to stop cancer.
The National Cancer Institute and Sloan Kettering Cancer Center have
both reported that tamoxifen causes mutations in endometrial cells,
including mutations in p53. More than one group has called for more
research in this area, but it hasn't been done.
There is evidence that tamoxifen causes another problem which hasn't
been adequately investigated. Constant exposure to the drug may
permanently alter the estrogen receptor. Receptors have "plasticity"-their
shape can change depending on what "fits in the door jamb." Tamoxifen
doesn't fit into the estrogen receptor just right. As a result, the
estrogen receptor changes its shape to fit tamoxifen. The same phenomenon
happens in people who chronically take mood-altering drugs. Their neurons
adapt to the drug. This is part of the phenomenon of drug tolerance and
withdrawal-the receptors have adapted to the artificial drug and depend on
it to function. No one knows whether tamoxifen permanently damages the
estrogen receptor in the same way.
These unknowns, coupled with the elevated risk of life-threatening
blood clots and uterine cancer, the lack of evidence that tamoxifen
prevents breast cancer at all in healthy women, plus the lack of an
accurate risk assessment tool of who is really at risk (see "Tamoxifen:
Cancer-causing Drug Approved for Healthy Women," Life Extension magazine,
May 1999), make tamoxifen risky as a cancer prevention strategy.
Indole-3-Carbinol: The
thinking person's cancer prevention
Tamoxifen is a chemical proven to provide short-term delay in the
reemergence of breast cancer in women who have already had breast cancer.
There is no evidence that it prevents breast cancer in women who have
never had it. There is evidence, however, that tamoxifen stops working
within months and starts feeding new, tamoxifen-dependent tumors, and
causes an elevated risk of uterine cancer and blood clots.
Despite these drawbacks, however, the drug possesses some very
desirable characteristics. It has powerful antioxidant action, plus the
ability to inhibit PKC. Its ability to block estrogen's "grow signal," and
stop cancer cells from growing are very important characteristics. Yet who
wants to take a drug that can potentially cause cancer and a host of other
ills? Is there anything better?
In 1991 researchers at the Institute for Hormone Research in New York
City announced that they had been able to induce the dy to convert the
stronger form of estrogen (estradiol) into a weaker form (2-hydroxy-
estrone) without using drugs. 2OHE is considered to be a more desirable
form of estrogen. It is less active than estradiol, so when it occupies
the estrogen receptor, it effectively blocks estradiol's strong "grow"
signals.
Natural substance changes the way estrogen is metabolized
It took only one week to prove that the conversion of estradiol to 2OHE
can be accomplished without drugs. Using a natural substance, researchers
were able to increase the conversion of estradiol to weak estrogen by 50%
in twelve healthy people.
Next, they tested the natural substance in female mice prone to
developing breast cancer. Both the incidence of cancer and the mber of
tumors fell significantly. What was the substance? Indole-3-carbinol
(IC3), a phytochemical isolated from cruciferous vegetables (broccoli,
cauliflower, Brussels sprouts, turnips, kale, green cabbage, mustard seed,
etc.).
I3C was then
given to 25 women for two months. Again, levels of strong estrogen
declined, and levels of weak estrogen increased. But more importantly, the
level of an estrogen metabolite associated with breast and endometrial
cancer (16alpha-hydroxyestrone) fell.
Product Information Continuation of Report: And more.
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