The NIH study spurred other scientists to look more closely at melatonin as an anticancer agent. Several researchers undertook to investigate whether melatonin could impede the growth of breast cancer tumors. In one study, researchers found that blind women who typically have higher levels of melatonin than normal, have a lower risk of developing breast cancer. Another study, performed by Steven M. Hill and David E. Blask at the University of Arizona, tested the effect of melatonin on a tissue culture of an estrogen-sensitive human breast cell tumor identified as MCF-7. They found that melatonin did indeed inhibit the growth of these cells by up to 78 percent. Other test tube studies have confirmed that melatonin can inhibit the growth of other kinds of tumor cells as well.
Melatonin not only inhibits the growth of tumor cells in test tubes. It also has been shown to block the growth of breast tumors in laboratory animals, which is significant because cancer grows and spreads in animals as it does in humans. In order to assess the effectiveness of a particular substance against cancer, one commonly used technique is to first administer a known carcinogen to an animal, and then administer the potential antidote. In several studies, researchers administered carcinogens known to produce mammary tumors in mice, rats, and hamsters. Then they administered melatonin. In most cases, melatonin either prevented the onset of cancer or significantly slowed down its growth.
As we mentioned earlier, prostate cancer is one of the leading causes of death among men over the age of fifty. The deaths due to prostate cancer of several prominent men in recent years, including Warner Communications CEO Steven Ross, and actors Telly Savalas and Bill Bixby, have called the attention to this often lethal disease. As in the case of breast cancer, the growth of prostate tumors may be accelerated by male hormone testosterone. Although there is no known cure for prostate cancer, it appears as if melatonin can slow down the progression of this disease. In a study conducted at the University of Texas Medical School, researchers found that melatonin could reduce by 50 percent rate of prostate tumors in rats, If melatonin works as well on human prostatic cancers, it could make a significant difference in the progression of this disease.
Melatonin may thwart the growth of hormone-sensitive tumors by normalizing the production of sex hormones; that, however, is not all it does. Melatonin attacks cancer cells in many different ways. One of the most potent ways to combat cancer is to black the process of cell division, thus nipping the troublesome cells in the bud. When a cell divides, it must undergo a complex sequence of events, one of which is the formation of what scientist’s call a spindle poisons. They prevent cells from forming a spindle and thereby prevent them from dividing. These drugs include Taxol, originally derived from the bark of the Pacific yew tree, which is used to treat lymphomas. Melatonin also interferes with spindle formation, thereby potentially inhibiting cell division. Thus it may prove to be another important weapon in our chemotherapy arsenal, but one that does not cause the unpleasant side effects that other chemotherapy drugs do.
There’s yet another intriguing way in which melatonin may be useful in the treatment of cancer. Studies have shown that melatonin can increase the number of estrogen receptors on human breast cancer cells. Receptors are cells that carry messages from hormones to cells; the hormone gives instructions to the cells via the receptors. Paradoxically, an increase in the number of estrogen receptors on breast cancer cells should promote the growth of breast tumors, and yet, for reasons unknown, in melatonin’s case it doesn’t. The capacity to increase estrogen receptors, however, can have some genuine therapeutic value. Tamoxifen, one of the most effective and commonly used drugs in the treatment of breast cancer, works by binding with estrogen receptors and inhibiting their effect on cell growth. About 60 percent of all breast tumors are estrogen-sensitive, and many women with these tumors do well on tamoxifen. However, over time, tamoxifen’s effectiveness can wear off, and other treatment options are limited. We propose that it may be possible to give melatonin to women who do not have estrogen-sensitive cancers to induce the growth of estrogen receptors so that these women can also respond to tamoxifen. Given the epidemic of breast cancer in the West, these ideas warrant further investigation.
Melatonin may also prevent the initiation of cancer by inhibiting the action of the initiators, the substances that inflict the initial cell damage that causes cells to mutate and become malignant. At the Third Strombli Conference on Aging and Cancer, noted pineal expert Dr. Russell Reiter reported that melatonin is a highly7 potent free-radical scavenger. Free radicals are unstable forms of oxygen molecules that can combine at random with components of healthy cells and interfere with normal growth. As we mentioned earlier, healthy cells divide in a methodical fashion. Healthy cells are programmed to know precisely to stop dividing. When the nucleus of a cell is injured, however, it loses its memory and begins to behave erratically. Cancer occurs when cells begin to grow out of control in a random fashion. The cellular damage inflicted by these free radicals can damage the cell nucleus, and thus promote many different forms of cancer. Free-radical scavengers are molecules that gobble up free radicals before they do any harm. Dr. Reiter’s observations and studies have revealed that melatonin appears to have an affinity for the nucleus of the cell where the DNA is stored. In other words, when melatonin passes through the cell, it finds its way to this important location. This has led some researchers, most notably Dr. Reiter, to speculate that melatonin’s specific task may be to protect DNA from the free –radical damage that can cause cancer. Although we find Dr. Reiter’s theory to be interesting, we feel that is probably overstates this particular aspect of melatonin. Some of the most innovative work on melatonin and cancer is being done outside the United States, in places such as San Gerardo hospital in Monza, Italy. There, our friend Dr. Paoli Lissoni, one of the most creative researchers in the field of cancer, has conducted some particularly promising studies involving melatonin. We think you should know about them. Lissoni’s group has used melatonin alone as a cancer treatment, and in combination with other forms of chemotherapy. In both cases, the results have been very encouraging. In one study, Lissoni gave only melatonin to patients with a variety of cancers that has already spread from other parts of the body to form inoperable brain tumors. These patients had little hope of recovery. However, those receiving melatonin along with supportive care fared significantly better than those just receiving supportive care. Specifically, those patients on melatonin lived longer and showed slower tumor progression that the untreated patients. In other studies, Lissoni and his co-workers have combined melatonin with interleukin-2 (IL-2), a natural disease-fighting compound produced by the immune system. In the 1980s, IL-2 was touted as a potential breakthrough in the treatment of certain types of cancers, and it is approved by the FDA for treatment of renal cancer in the United States. However, the side effects of IL-2 are nothing short of terrible. This Drug, which is quite toxic, can produce high fevers, chills water retention, swelling and other problems. IL-2 may do a good job of wiping out cancer cells, but few patients can tolerate its side effects. Lissoni, however, devised an ingenious approach. HE used a lower and less toxic dose of IL-2 and combined it with melatonin. He administered Il-2/melatonin to patients with a wide variety of cancers, including kidney, stomach and liver cancer and even melanoma. Once again, these were patients who had little hope of long term survival. After the IL-2/melatonin program, many of these patients showed marked improvement, their tumors regressed, their appetites returned, and they seemed to be generally doing better. A handful of patients even appeared to experience partial remission. Moreover, the melatonin was able to virtually eliminate the severe side effects of IL-2, making the immunotherapy treatment more tolerable. Follow-up studies have showed that although the IL-2/melatonin regimen did not result in any miracle cures, it did appear to extend the lives of many patients, and perhaps, more importantly, to improve the quality of their lives.
One of Lissoni’s most interesting studies established a link between melatonin levels and patient response to cancer therapy. In his study of forty-two chemotherapy patients, Lissoni tested their melatonin levels before chemotherapy and also four weeks after the end of their treatment . Lissoni found a direct correlation between patient improvement and a rise in melatonin levels. Out of the sixteen patents who had shown a rise in melatonin levels, tumors shrank in twelve and did not progress in the rest. Out of the twenty-six patients who had shown a rise in melatonin levels, tumors shrank in twelve and did not progress in the rest. Out of the twenty-six patients who had shown a continuous fall in melatonin, only two showed any improvement. Melatonin levels may indeed be a marker that can help doctors predict the prognosis of their cancer patients.
In addition to Lissoni’s work, there are other examples of how melatonin may enhance the effect of traditional chemotherapy, while sparing patients some of its horrendous side effects. Under the direction of Dr. Bruno Neri, researchers at the University of Florence in Italy tested the effect of melatonin combined with another anticancer drug, human lymphoblastoid intereron (HLI). HLI is a natural protein that can kill viruses and cancer cells, but also causes miserable side effects, including fever, chills, and muscle aches. In Neri’s study, twenty-one patients with progressive renal cell carcinoma – a particularly insidious form of kidney cancer that can spread quickly, and is often unresponsive to chemotherapy – were given HLI and melatonin. In past studies, HLI had been shown to be only mildly effective against this cancer. When combined with melatonin, however, the HLI appeared to work better, and the side effects were lessened. In fact, in three patients the tumors disappeared completely, although only follow-up studies will show if this is a true and lasting cure. Four patients showed partial remissions. As of this writing, Neri is conducting a larger study to determine if HLI and melatonin will prove to be an effective treatment for this potentially deadly form of cancer.
The studies that we’ve just described show that melatonin, when combined with traditional chemotherapy, not only can improve the performance of anticancer drugs, but can also lessen the severity of side effects, and actually makes the patients feel better. This makes perfect sense given what we know about melatonin. Our studies have shown that melatonin works in combination with the natural opiates or painkillers produced in our bodies. When we’re sick and under a great deal of stress, or in pain due to an injury, our bodies produce chemical compounds called endorphins, which help relieve pain. The immune system is instrumental in the release of certain endorphins, and in fact, these hormones may also play a role in healing. Such studies suggest that melatonin may work in tandem with these natural opiates, and may enhance their action. Perhaps this is why the cancer patients felt better when taking melatonin. In fact, it’s also possible that when melatonin is combined with other narcotics or tranquilizers, there might be a synergistic effect, that is, the two combined may be stronger than the effect of any one alone. In this respect, melatonin may be beneficial for cancer patients, or any patients suffering pain, since it decreases the need for narcotics and minimizes negative side effects.
One o the problems with many of the most effective forms of chemotherapy is that the cure is almost as bad as the disease itself in terms of the harm it can inflict on the body. By necessity, chemotherapy drugs must be strong enough to knock out cancer cells, and very often they also destroy healthy cells in the process. For example, some anticancer drugs can destroy the blood-forming cells in the bone marrow, which can result in severe anemia, and can inflict untold damage on the immune system. We investigated whether melatonin might actually protect the bone marrow from this kind of damage. With Vladimir Lesnikov in St. Petersburg, we tested the toxicity of several chemotherapy agents on the bone marrow cells suffered far less damage. This is yet another aspect of melatonin that is worthy of further investigation.
Our findings are consistent with those of other researchers who have
shown that chemotherapy is often more effective and less toxic when given
at night, presumably because melatonin levels are at their peak. In fact,
many chemotherapy patients are now given intravenous pumps with timers
that automatically pulse anticancer drugs into their bodies while they
sleep. Thanks to this innovation, many of these patients are now able
to get their chemotherapy treatments in the comfort of their own home,
which is a much more natural and relaxing setting than a hospital. This
also means that the treatment does not disrupt normal sleep patterns – and
nighttime melatonin production which can be disturbed by the bright lights
and noise of a busy hospital.
Melatonin as biological response modifier in cancer patients
Neri B, de Leonardis V, Gemelli MT, di Loro F, Mottola A, Ponchietti R, Raugei A, Cini G
Oncological Day Hospital, Department of Internal Medicine, University of Florence, Italy
The neuroendocrine system modulates the immune response through neuropeptides
and neurohormones, findings which point to the existence of a neuro-endocrine-immune
system regulatory axis.
PMID: 9615811 [PubMed - indexed for MEDLINE]
Side Effects, Toxicity and Interactions:
Large doses of melatonin may interfere with ovarian function. Definite interference with sexual development has been demonstrated in animals given supplements of melatonin.
Avoid driving or operating machinery for several hours after taking melatonin. The natural secretion of melatonin is possibly affected by stimulants, including coffee, late night exercise, late night snacks and light in the bedroom.
There are no known significant food or drug interactions.
Lissoni P, Meregalli S, Nosetto L, et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology. 1996;53:43-46.
Lissoni P, Paolorossi F, Ardizzoia A, et al. A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. J Pineal Res. 1997;23:15-19.
. Lissoni P, Tancini G, Barni S, et al. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Support Care Cancer. 1997;5:126-129.
Neri B, de Leonardis V, Gemelli MT, et al. Melatonin as biological response modifier in cancer patients. Anticancer Res. 1998;18:1329-1332.
Neri B, de Leornardis V, Gemelli MT. Melatonin as biological response modifier in cancer patients. Anticancer Res. 1998;18:1329-1332.
Garfinkel D, et al. Improvement of sleep quality in elderly people by controlled-released melatonin. Lancet. 1995;346:541-544.
Haimov I, et al. Sleep disorders and melatonin thythms in elderly people. BMJ. 1994;309:167.
Lissoni P, Tancini G, Barni S. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Support Care Cancer. 1997;5:126-129.
Waterhouse J, et al. Jet lag. Lancet. 1997;350:1611-1616.
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