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. I’m from the Mary Imogene Bassett Hospital Research Institute in beautiful Cooperstown, New York, at the southern end of Otsego Lake in upstate New York. I’ve been working for about 20 years now on the pineal gland and particularly the hormone melatonin in relationship to cancer, particularly breast cancer. I’d like to discuss with you today the work that we’ve 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 tamoxifen’s effect on breast cancer. I’ll show you some evidence that may suggest that melatonin may reverse tamoxifen resistance. I’m going to take you through our laboratory bench studies to the bedside. Along the way I’ll take you on a little tour through the pineal gland and how melatonin is produced, what it does. Then, I’ll take you through our laboratory studies and some of the published clinical studies. All the studies that I’m 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. You’ve 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 don’t 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 it’s 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 melatonin’s 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 I’m going to talk about. Light suppresses melatonin production. The nighttime production of melatonin declines with age. By the time you’re around 80 years old, you’re 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 it’s dark. Obviously our liver doesn’t 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. What’s the relationship with breast cancer? A study done back in the early 80’s 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. I’ll tell you why in a second. Here’s tumor growth, breast cancer growth, in the animals receiving the vehicle. Here’s 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, there’s 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 – these are physiological – 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 there’s a relationship between estrogen, the estrogen receptor, and the ability of melatonin to inhibit cancer growth. This shows the ability of estrogen (a physiological amount) to stimulate breast cancer growth, again in a petri dish. Here’s 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 estradiol’s 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 it’s 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. Here’s 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 wouldn’t 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. I’m 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 they’re not very well done. One is randomized, but they’re not double-blind and placebo-controlled trials. They take what we’ve 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 o’clock. 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 duration of 14 months. This suggests that melatonin somehow resensitized their tumors to tamoxifen. This goes along with our laboratory data. I’ll 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 survival. 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 |
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