Comprehensive Cancer Care: Integrating Complementary & Alternative Therapies
New Therapies in Breast Cancer- Melatonin
Center For Mind Body Medicine 1998 Conference
Moderator: Devra Lee Davis, PhD, MPH
Presenters: David Blask, MD, PhD
Dr. Blask: Thank you very much. My name is Dave Blask. Iím from the Mary
Imogene Bassett Hospital Research Institute in beautiful Cooperstown, New
York, at the southern end of Otsego
Lake in upstate New York.
Iíve been working for about 20 years now on the pineal gland and
particularly the hormone melatonin in relationship to cancer, particularly
breast cancer. Iíd like to discuss with you today the work that weíve done
in the laboratory. It has extended to some clinical trials in Europe
suggesting that the hormone melatonin produced in the pineal gland may be a
promising agent in combination with tamoxifen to enhance tamoxifenís effect
on breast cancer.
Iíll show you some
evidence that may suggest that melatonin may reverse tamoxifen resistance.
Iím going to take you through our laboratory bench studies to the bedside.
Along the way Iíll take you on a little tour through the pineal gland and
how melatonin is produced, what it does. Then, Iíll take you through our
laboratory studies and some of the published clinical studies. All the
studies that Iím going to show you are published in the scientific
peer-reviewed literature unless indicated otherwise.
This is a prototypical breast cancer cell, actually an estrogen receptor
positive (ER+) breast cancer cell. It illustrates the fact that breast
cancer cells are literally bombarded with growth factor signals that
stimulate the growth of these cells. Youíve already heard about estrogen being
a very prominent stimulator of cell growth. We think that melatonin may be
a direct inhibitory signal, a naturally occurring substance produced by the
body, produced by the brain, that may serve to counteract some of these
growth-stimulatory signal effects.
One of the mainline treatments for
breast cancer is tamoxifen, which has been mentioned already by Dr. Barnes.
About 50 to 60% of all breast cancers are ER+ -- and ER+ breast cancers are
the most responsive to tamoxifen.
However, 40% of ER+ breast cancers donít respond to tamoxifen. About 10% of
estrogen receptor negative (ER-) do respond to tamoxifen. The current
thought is that tamoxifen somehow
blocks the action of estrogen at the level of its receptor. The tamoxifen
story (in terms of its mechanism of action) is turning out to be much more
complicated than we had originally
anticipated. Although itís an excellent drug as drugs go, a problem with
tamoxifen is either de novo or acquired resistance. Eventually all women
who are on tamoxifen will become resistant to it. This is where melatonin
comes into this story.
The pineal gland may have a very important interaction through
melatonin on the growth of breast cancer through a variety of levels,
including influences on the brain, influencing hormones produced by the
brain, as well as a direct effect of melatonin itself on breast cancer,
which we believe is its primary mode of action. The pineal gland is located in
the geographic center of the brain. Everyone has a pineal gland, and
virtually all vertebrate species have pineal glands, and they produce
melatonin. One of melatoninís main functions is to act as part of a very
complex biological clock system, in terms of biological timing of
physiological and probably pathophysiological processes. Influencing this
biological clock system is the light/dark cycle.
Melatonin is produced during darkness. Light or darkness through the eyes
influences the pineal gland to produce this hormone melatonin through a
very complex set of nerve pathways that eventually impinge upon the pineal
gland, again in the center of the brain. This shows you that during the
nighttime we produce a melatonin signal. These are individuals and their
nighttime melatonin signal. If you introduce light during the darkness,
light will shut off the ability of the pineal gland to produce melatonin.
This has important implications for some of the tumor studies that Iím
going to talk about. Light suppresses melatonin production.
The nighttime production of melatonin declines with age. By the time youíre
around 80 years old, youíre barely producing any melatonin during the
night. There is age-related decline. How long melatonin is elevated during
the night literally tells all the organs and cells of the body that itís
dark. Obviously our liver doesnít have eyes. Through the nighttime
melatonin signal all the cells of the body know that it is dark, or when
melatonin is very low, know that it is light. The pineal gland, through the
melatonin signal, is a clock. If you live in extremes of latitude like the
northeast or the northwest, for example, during the long nights of winter
the duration of the melatonin signal becomes longer. During the spring and
summer the signal becomes shorter. The melatonin signal is also part of a
calendar system involving the pineal gland. The pineal gland is both a
clock and a calendar.
Whatís the relationship with breast cancer? A study done back in the early
80ís demonstrated that the nighttime melatonin signal in women with ER+
breast cancer was severely blunted as
compared with normal healthy age-matched women, as well as women with ER-
breast cancer. This suggested that there must be some important
relationship between breast cancer and the
melatonin rhythm. Another group of German colleagues demonstrated that in
breast cancer this nighttime signal was blunted. The degree of the blunting
of that nighttime surge correlated with the size of the tumor. The larger
the tumor, the bigger the decrease in the nighttime rise in melatonin,
again suggesting an important relationship.
In our own studies, using a carcinogen called NMU, we injected animals with
either a placebo or a vehicle or melatonin, 250 micrograms per day. We
injected it in the afternoon, a few hours before lights off. This is very,
very important. Iíll tell you why in a second. Hereís tumor growth, breast
cancer growth, in the animals receiving the vehicle. Hereís tumor growth in
the animals receiving the afternoon melatonin injections. If we inject
melatonin, the same dose, during the morning a few hours after the lights
go on in the animal room, thereís no effect of melatonin. There is a time
of day sensitivity to the anticancer effect of melatonin in this model. If
we remove the pineal glands from animals, you can see that removing that
normal melatonin signal that these animals experience during the night
allows their tumors to grow or develop in much greater manner. It enhances
tumor development. If we put animals on constant light, which
also knocks out the melatonin signal, we see a very similar effect. The
endogenous melatonin signal, as well as exogenous melatonin, can inhibit
cancer growth in this mode.
When we look at the growth of human breast cancer cells, particularly ER+
breast cancer cells in the petri dish, if we expose these cells to
melatonin for seven days, and we expose them to concentrations of melatonin
that are present in the blood during the nighttime Ė these are
physiological Ė you can see that, compared to control cells without
melatonin, the growth is inhibited quite substantially. There is a direct
effect of melatonin on human breast cancer cell growth in vitro, or in the
petri dish. To emphasize, estrogen is important, and thereís a relationship
between estrogen, the estrogen receptor, and the ability of melatonin to
cancer growth. This shows the ability of estrogen (a physiological amount)
to stimulate breast cancer growth, again in a petri dish.
Hereís the effect of melatonin compared to the control cells, by itself an
inhibitory effect. If we combine melatonin with estradiol you can see that
melatonin inhibits estradiolís ability to stimulate the growth of those
cells, so it has an anti-estrogen effect. But I must emphasize that the
mechanism is very different from tamoxifen. We see a similar effect when we
again go back to that carcinogen model, where we inject the animals with a
carcinogen. This represents estrogen-stimulated growth of these tumors. If
we combine melatonin at several different doses with estradiol, you can see
that estradiol completely blocks this stimulation with estrogen in these
animals. In fact itís as effective as tamoxifen in this particular study.
There is an anti-estrogen effect of melatonin in these models. We did an
experiment where we were trying to figure out some of the mechanisms by
which melatonin interacts with the estrogen receptor. We treated cells with
either estrogen or tamoxifen or combinations of these agents as well as
melatonin. We found when we initially treated cells with tamoxifen, and
stuck in estrogen a couple of days later, that we could partially reverse
the effects of tamoxifen. Tamoxifen by itself had an inhibitory effect.
Melatonin by itself had an inhibitory effect. We found that estrogen
treatment reversed the effects of melatonin. What we noticed was very
interesting was that when we combined tamoxifen with melatonin in the
presence of estradiol, we got a greater inhibitory effect than either of
the two alone. There seemed to be an enhancing
effect of the combination of tamoxifen and melatonin. Melatonin sensitized
breast cancer cells to the actions of tamoxifen.
In the next experiment, we took cells and just exposed them to three
different doses of tamoxifen. This dose is equivalent to what is used
clinically to treat breast cancer. This again is in the petri dish. We
pretreated another group of cells with melatonin at a physiological level
for 24 hours and then we washed out the melatonin and exposed those
melatonin pretreated cells to the tamoxifen. Hereís the inhibition of
breast cancer cell growth in cells that were not pretreated
with melatonin. Tamoxifen has a very substantial inhibitory effect. But
look at the effect of tamoxifen in those cells that were pretreated with
melatonin. Melatonin enhanced the effects of tamoxifen in inhibiting cell
growth. This suggested to us that melatonin does sensitize breast cancer
cells to the inhibitory effects of tamoxifen and that these two agents
might be used in some combination to the advantage of the patient eventually.
We took this one step further and took another animal model. We took a nude
mouse, which is devoid of an immune system. It allows us to transplant
human cancer cells into the mouse and
grow solid human tumors. What we did in this model was inject animals
either with a vehicle, with a very low dose of melatonin (which would not
inhibit tumor growth), with a very low dose of tamoxifen (which wouldnít
have very much of an inhibitory effect alone on tumor growth), or the
combination of the two. Melatonin itself had virtually no inhibitory effect
at this low dose. The low dose of tamoxifen by itself had a modest
inhibitory effect compared to control animals.
However, when we used the two in combination, we saw what appears to be a
synergistic effect. We interpret this as an enhancing effect of melatonin
on tamoxifen action. This is an unpublished study, by the way.
Iím going to finish up by showing you the results of two clinical trials
that were done in 1995 and published in The British Journal of Cancer by an
Italian group. These are small clinical trials. You could argue that
theyíre not very well done. One is randomized, but theyíre not double-blind
and placebo-controlled trials. They take what weíve done in the laboratory
the next step and are very provocative. They took 14 patients that were
either ER+ or ER- and had metastatic breast cancer, and they had been
treated with tamoxifen. Ten had stable disease in response to tamoxifen,
and then they developed resistance. The remaining four patients were
refractory to tamoxifen right out of the gate.
All of these patients became refractory to tamoxifen, they had resistance.
They took these patients off of tamoxifen for about a month, and then
started them on melatonin, giving them oral melatonin in the evening, at 8
oíclock. They were giving the tamoxifen, 20 milligrams, at noon. They gave
the melatonin alone for a week and then started them back on tamoxifen. You
can see that this combination of melatonin with tamoxifen resulted in
stable disease in 57% or eight of the patients. A partial response, or
partial regression was achieved in four of the patients, and progressive
disease in two of the patients. Ten of the 14 patients survived a median
14 months. This suggests that melatonin somehow resensitized their tumors
to tamoxifen. This goes along with our laboratory data.
Iíll share just one more clinical study to finish up. The same group did a
randomized study. This was not double-blind or necessarily
placebo-controlled. They took ER- patients, a total of 40 of them, and put
half of them on melatonin and tamoxifen in combination, and the other half
on tamoxifen only. They found that apparently with tamoxifen alone, the
one-year survival was 37%; however in combination with tamoxifen, melatonin
seemed to produce a larger one-year
There appears to be some data, from the bench to the bedside, indicating
that melatonin may be, in combination with tamoxifen, a new alternative
therapy for the treatment of breast cancer. Obviously this has to be
investigated much more thoroughly, but it suggests that melatonin may
reduce the toxicity while enhancing the efficacy of tamoxifen, and may be
helpful in solving some of the problems of acquired tamoxifen resistance.
Thanks to the Mid Hudson Options Project