Life Extension Magazine®

Issue: Mar 2001

In The News

SAMe works, aspirin and Alzheimer’s, etc.

Lovastatin shows potent anti-cancer effects

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In 1997, The Life Extension Foundation published a protocol suggesting that cancer patients ask their oncologist to consider prescribing the drug lovastatin (80 mg a day) as an adjuvant therapy. This recommendation was based on scientific studies indicating that lovastatin interfered with the cancer cell growth cycle and might be synergistic with conventional therapies in inducing apoptosis (programmed cell death). Since 1997, a number of studies have substantiated the potential benefit of lovastatin in treating a wide range of cancers. In a new study published in the journal Clinical Cancer Research (January 2001), lovastatin demonstrated pronounced effects in inducing cancer cell apoptosis in certain types of cancer. The scientists who conducted this study showed that lovastatin worked particularly well in the following cancer cells: acute myeloid leukemia, neuroblastoma, squamous cell carcinoma of the cervix, juvenile monomyelocytic leukemia, head and neck squamous cell carcinoma, medullobastoma and rhabdomyosarcoma. In discussing the results of their most recent research, the scientists pointed to a previous five-year study on 745 people taking lovastatin (to reduce their high cholesterol) that showed that these subjects had a lower than expected incidence of cancer. Most interesting was that in this group of 745 people taking lovastatin for 5-years, the incidences of prostate and breast cancer was as expected, whereas there were no cases of lovastatin-sensitive cancers observed. The scientists suggested that these findings indicated that lovastatin may prevent certain types of cancer from developing in the first place. In this study published in Clinical Cancer Research , the scientists noted that "lovastatin has the potential as an immediate, novel therapeutic approach in the treatment of these responsive tumors. Lovastatin induced a specific apoptotic response in these tumor cells within achievable therapeutic range and it (lovastatin) has a proven record in the clinic as a safe and effective drug." The scientists related a case history of a patient with acute myeloid leukemia treated at their institution using lovastatin at the high dose of 2 milligrams per kilogram of body weight per day for 52 consecutive days. For a person weighing 154 pounds, this would mean a daily dose of lovastatin of 140 mg. The patient taking this high-dose lovastatin demonstrated control of leukemic blast counts that lasted more than six months after cessation of treatment.

There are now Phase I clinical trials scheduled to evaluate the toxicity and efficacy of low-dose lovastatin in the treatment of recurrent acute myeloid leukemia, head and neck squamous cell carcinomas, and cervical cancer. The Life Extension Foundation does not recommend that members enter these Phase I clinical trials, as they will restrict the use of other synergistic cancer therapies and may use a dose of lovastatin too low to provide optimal benefit. Instead, members should ask there doctor to prescribe a higher dose lovastatin and have a complete blood chemistry test performed every two weeks for the first two months of therapy to make sure lovastatin is not causing liver or muscle damage. Monthly blood chemistry tests should be done as long as high dose lovastatin is used.

Previous studies have indicated that lovastatin and other fat-soluble "statin" drugs are also effective against pancreatic, colon, liver and thyroid tumors. There are several mechanisms of action that have been proposed for lovastatin's anti-cancer actions, including suppressing the over-expression of the RAS oncogene and interfering with the mevalonate pathway used by some cancer cells in the G1 phase of the cell cycle. Lovastatin (sold under the trade name Mevacor) is one fat-soluble "statin" drug available by prescription. Other fat-soluble statin drugs include Zocor and Lipitor. The popular cholesterol-lowering drug called Pravachol is a water-soluble "statin" that may not work as well against cancer as the fat-soluble "statin" drugs. For further information on the use of "statin" drugs to treat cancer refer to the Cancer (Adjuvant) Treatment section of the book Disease Prevention and Treatment or view this protocol on the Foundation's website at www.lifeextension.com

Soy and DHEA make women happy

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Japanese researchers have reported that the benefits of soy may include psychological well-being. Women who eat soy products are less anxious, fearful and depressed, according to a new study. All the women who participated were healthy, and none were on hormone replacement therapy. The beneficial effects of soy may be due to its estrogen-like actions. Genistein, a component of soy, interacts with estrogen and GABA receptors in the brain. Information was obtained from 103 Japanese women, average age 54. The women then completed the Center for Epidemiologic Studies Depression (CES-D) Scale and the psychological part of the General Health Questionnaire (GHQ). Women who ate the most soy scored the best on these tests. Neither estradiol nor sex hormone binding globulin correlated with mood, but dehydroepiandrosterone did. DHEA, as it is known, was also higher in the study participants who were happier. It's unknown whether there is a correlation between soy and DHEA, but previous studies have shown a positive effect of DHEA on mood in older people.

DHEA is an androgen-type hormone that is converted to both estrogen and testosterone. Testosterone increases libido in some women. Estrogen replacement therapy (drug therapy) has proven beneficial in enhancing mood in some older women. According to a meta-analysis published in 1999, “At this time, estrogen therapy [synthetic estrogen drugs] for the treatment of depression in peri and postmenopausal women may be useful, but confirmatory studies are still lacking.” The possible benefits of drug therapy should be weighed against the risks and side effects, which are substantial.

Reference

Archer JS. 1999. NAMS/Solvay Resident Essay Aware. Relationship between estrogen, serotonin, and depression. Menopause 6:71-8.

Morales AJ, et al. 1994. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 78:1360-67.

Nagata C, et al., 2000. Serum concentrations of estradiol and dehydroepiandrosterone sulfate and soy product intake in relation to psychologic well-being in peri and postmenopausal Japanese women. Metabolism 49:1561-64.

Wolkowitz OM, et al. 1995. Antidepressant and cognition-enhancing effects of DHEA in major depression. Ann NY Acad Sci 774:b337-39.

I3C and breast cancer

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A new study confirms that invasive breast cancer is less likely to occur when the body converts estrogen a certain way. The study reports a 40% reduction in risk when the body metabolizes estrogen into the less potent 2-hydroxyestrone instead of 16a-hydroxyestrone. These metabolites have important differences, one being that 16a-hydroxyestrone has stronger estrogenic activity than 2-hydroxyestrone which is a weak form of estrogen. The more 2-hydroxyestrone a woman has in her body, the less likely she will have the strong 16a-hydroxyestrone that can drive cancer growth. The findings are based on data from 144 Italian women with breast cancer out of 10,000 who participated in a study on how hormones and diet might cause the disease. 16a-hydroxyestrone is higher in women with breast cancer, and correlates with a greater incidence of mammary tumors in mice.

One of the things that changes the way estrogen is metabolized is indole-3-carbinol (I3C), a substance in cruciferous vegetables such as cabbage, cauliflower and broccoli. I3C has been purified, and is sold as a supplement. In studies where the supplement is used, I3C causes an increase in the amount of 2-hydroxyestrone. That in turn, puts a damper on cancer growth encouraged by 16a-hydroxyestrone. I3C doesn't affect 16a-hydroxyestrone directly. Studies show that I3C can also reduce DNA damage caused by heterocyclic amines (cancer-causing molecules that arise when meat is cooked), and cigarette smoke. It also inhibits the formation of 4-hydroxyestrone which is carcinogenic. In cancer cells, it induces apoptosis (cell death), and stops the cell cycle. In mice, I3C prevents cervical cancer caused by papilloma virus. It may also affect the growth of prostate cancer (although studies have not been done). A male hormone, 16a-hydroxytestosterone, is transformed through the same mechanism as 16a-hydroxyestrone in women.

Reference

Arif JM, et al. 2000. Inhibition of cigarette smoke-related DNA adducts in rat tissues by indole-3-carbinol. Mutat Res 452:11-18.

He YH, et al. 2000. Indole-2-carbinol as a chemopreventive agent in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) carcinogenesis: inhibition of PhIP-DNA adduct formation, acceleration of PhIP metaqbolism, and induction of cytochrome P450 in female F344 rats. Food Chem Toxicol 38:15-23.

Jin L, et al. 1999. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res 59:3991-97.

Muti P, et al. 2000. Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16 -hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology 11:635-40.

Schneider JD, et al. 1982. Abnormal oxidative metabolism of estradiol in women with breast cancer. Proc Natl Acad Sci USA 79:3047-51.

SAMe works when other anti-depressants fail

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In a study published in the journal Movement Disorders (Nov 15, 2000), s-adenosyl-methionine (SAMe) was administered to 13 depressed patients with Parkinson's disease. All patients had been previously treated with other antidepressant agents and had no significant benefit or had intolerable side effects. SAMe was administered in doses of 800 to 3600 mg per day for a period of 10 weeks. Eleven patients completed the study, and 10 had at least a 50% improvement on the 17-point Hamilton Depression Scale. One patient did not improve. Two patients prematurely terminated participation in the study because of increased anxiety. One patient experienced mild nausea, and another two patients developed mild diarrhea, which resolved spontaneously. The mean improvement in depression scores from before to after treatment was approximately 64%.

Although this study was uncontrolled and preliminary, it suggests that SAMe is well tolerated and may be a safe and effective alternative to the antidepressant agents currently used in patients with Parkinson's disease. Please note that some of these Parkinson's patients received very high doses of SAMe, which could account for the few side effects observed. Previous clinical studies show that doses of 800 to 1600 mg a day of SAMe produce remarkable anti-depressant benefits in otherwise healthy people without significant side effects.

Aspirin & Alzheimer's

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In the November 2000 issue of Life Extension we reported that ibuprofen, aspirin and other anti-inflammatories slow the progression of Alzheimer's disease (AD). People who chronically take anti-inflammatory drugs lower their risk of getting AD in the first place. Most studies have looked at people who take non-steroidal anti-inflammatory drugs (NSAIDs) for other conditions such as rheumatoid arthritis. Most of these people are taking moderate to high doses. A new study looks at whether or not lower doses of NSAIDs and other anti-inflammatories also reduce risk. It was found that they do, at least in people over 75. As in previous studies, aspirin seems to work about half as well as NSAIDs such as ibuprofen-but it still can reduce risk about 25%.

High doses are not needed for beneficial effects. Aspirin in doses less than 175 mg/day and NSAIDs in doses less than 500 mg/day provide protection against AD. This is good news for people worried about intestinal bleeding and potential kidney damage (the latter due to high-dose NSAIDs). The very group that is most at risk for AD (over age 75) is also more likely to get serious side effects from anti-inflammatories.

The fact that it only takes low doses of the drugs to get the effects means, also, that anti-inflammatories work by some mechanism other than reducing inflammation. The authors suggest that low levels of anti-inflammatories may work by inhibiting the release of b-amyloid from platelets and/or by inhibiting excess levels of cyclooxygenase (COX).

A surprising finding of the study was the strong showing of ACE-inhibitors. Taking these drugs also appears to lower the risk of Alzheimer's. ACE (which stands for “angiotensin converting enzyme”) inhibitors are used to treat heart disease and lower blood pressure.

The study, conducted in Sydney, examined 78 patients with probable AD (as assessed by National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria). It also looked at 45 people with possible AD and/or vascular dementia, and 40 people with other dementias. The effects of anti-inflammatories held up only for AD, not for dementias of other types. The study did not, however, look at duration. In other words, we don't know how long a person has to take anti-inflammatories to get the beneficial effects. Other studies suggest that a person has to take NSAIDs for years, while aspirin may start working immediately. (Two plus years of NSAID use in the Baltimore Longitudinal Study of Aging reduced the risk 60%). While this question is still up-in-the-air, it seems that the question of whether a person can get anti-Alzheimer's effects by taking low doses of anti-inflammatories has been answered in the affirmative for now.

Reference

Anthony JC, et al. 2000. Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County study. Neurology 54:2066-71.

Broe GA, et al. 2000. Anti-inflammatory drugs protect against Alzheimer [sic] disease at low doses. Arch Neurol 57:1586-91.

Stewart WF, et al. 1997. Risk of Alzheimer's disease and duration of NSAID use. Neurology 48:626-32.

Sugaya K, et al. 2000. New anti-inflammatory treatment strategy in Alzheimer's disease. Jpn J Pharmacol 82:85-94.

All in the Genes

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Genetics' contribution to the risk of breast, colorectal and prostate cancer is 27%, 35% and 42% respectively, according to a study of 44,788 pairs of twins from Scandinavian registries, published in the New England Journal of Medicine last summer. But for most of more than 15 other anatomic sites, the study found little or no genetic contribution to risk.

This study sheds additional light on a controversy that has raged over the genetic vs. environmental contribution to cancer, Robert M. Hoover, M.D., of the National Cancer Institute wrote in an editorial accompanying the article. Most researchers agree that 80% to 90% of human cancer is environmentally caused. The findings, Hoover writes, are consistent with the literature behind this consensus, including studies of certain cancers among immigrant populations that come to match rates in the new homeland after several generations. Nonetheless, the discovery over the last 15 years of the genetic mechanisms underlying cancer has overshadowed environmental explanations in the minds of researchers, doctors, policymakers and the public, according to Hoover.

For cancer researchers, the most intriguing implication is that “there must be major gaps in our understanding of the genetic basis of colorectal, breast and prostate cancer.” According to the authors, who were led by Paul Lichtenstein of the Karolinska Institute, Stockholm, the frequency of known high-risk mutations is insufficient to account for observed rates of these cancers in the study. Hoover adds that the nature/nurture debate obscures the fact that “. . .genes and environment interact to produce a risk greater than the sum of their independent effects,” which can be reduced by advances in either area. For health-care professionals and individuals who wish to take charge of their health, the message is an optimistic one: genetics is not destiny.

-David Holtzman


In The News

SAMe works when other anti-depressants fail

imageIn a study published in the journal Movement Disorders (Nov 15, 2000), s-adenosyl-methionine (SAMe) was administered to 13 depressed patients with Parkinson's disease. All patients had been previously treated with other antidepressant agents and had no significant benefit or had intolerable side effects. SAMe was administered in doses of 800 to 3600 mg per day for a period of 10 weeks. Eleven patients completed the study, and 10 had at least a 50% improvement on the 17-point Hamilton Depression Scale. One patient did not improve. Two patients prematurely terminated participation in the study because of increased anxiety. One patient experienced mild nausea, and another two patients developed mild diarrhea, which resolved spontaneously. The mean improvement in depression scores from before to after treatment was approximately 64%.

Although this study was uncontrolled and preliminary, it suggests that SAMe is well tolerated and may be a safe and effective alternative to the antidepressant agents currently used in patients with Parkinson's disease. Please note that some of these Parkinson's patients received very high doses of SAMe, which could account for the few side effects observed. Previous clinical studies show that doses of 800 to 1600 mg a day of SAMe produce remarkable anti-depressant benefits in otherwise healthy people without significant side effects.

Aspirin & Alzheimer's

In the November 2000 issue of Life Extension we reported that ibuprofen, aspirin and other anti-inflammatories slow the progression of Alzheimer's disease (AD). People who chronically take anti-inflammatory drugs lower their risk of getting AD in the first place. Most studies have looked at people who take non-steroidal anti-inflammatory drugs (NSAIDs) for other conditions such as rheumatoid arthritis. Most of these people are taking moderate to high doses. A new study looks at whether or not lower doses of NSAIDs and other anti-inflammatories also reduce risk. It was found that they do, at least in people over 75. As in previous studies, aspirin seems to work about half as well as NSAIDs such as ibuprofen-but it still can reduce risk about 25%.

High doses are not needed for beneficial effects. Aspirin in doses less than 175 mg/day and NSAIDs in doses less than 500 mg/day provide protection against AD. This is good news for people worried about intestinal bleeding and potential kidney damage (the latter due to high-dose NSAIDs). The very group that is most at risk for AD (over age 75) is also more likely to get serious side effects from anti-inflammatories.

The fact that it only takes low doses of the drugs to get the effects means, also, that anti-inflammatories work by some mechanism other than reducing inflammation. The authors suggest that low levels of anti-inflammatories may work by inhibiting the release of b-amyloid from platelets and/or by inhibiting excess levels of cyclooxygenase (COX).

A surprising finding of the study was the strong showing of ACE-inhibitors. Taking these drugs also appears to lower the risk of Alzheimer's. ACE (which stands for “angiotensin converting enzyme”) inhibitors are used to treat heart disease and lower blood pressure.

The study, conducted in Sydney, examined 78 patients with probable AD (as assessed by National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria). It also looked at 45 people with possible AD and/or vascular dementia, and 40 people with other dementias. The effects of anti-inflammatories held up only for AD, not for dementias of other types. The study did not, however, look at duration. In other words, we don't know how long a person has to take anti-inflammatories to get the beneficial effects. Other studies suggest that a person has to take NSAIDs for years, while aspirin may start working immediately. (Two plus years of NSAID use in the Baltimore Longitudinal Study of Aging reduced the risk 60%). While this question is still up-in-the-air, it seems that the question of whether a person can get anti-Alzheimer's effects by taking low doses of anti-inflammatories has been answered in the affirmative for now.

image


Anthony JC, et al. 2000. Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County study. Neurology 54:2066-71.

Broe GA, et al. 2000. Anti-inflammatory drugs protect against Alzheimer [sic] disease at low doses. Arch Neurol 57:1586-91.

Stewart WF, et al. 1997. Risk of Alzheimer's disease and duration of NSAID use. Neurology 48:626-32.

Sugaya K, et al. 2000. New anti-inflammatory treatment strategy in Alzheimer's disease. Jpn J Pharmacol 82:85-94.


All in the Genes

imageGenetics' contribution to the risk of breast, colorectal and prostate cancer is 27%, 35% and 42% respectively, according to a study of 44,788 pairs of twins from Scandinavian registries, published in the New England Journal of Medicine last summer. But for most of more than 15 other anatomic sites, the study found little or no genetic contribution to risk.

This study sheds additional light on a controversy that has raged over the genetic vs. environmental contribution to cancer, Robert M. Hoover, M.D., of the National Cancer Institute wrote in an editorial accompanying the article. Most researchers agree that 80% to 90% of human cancer is environmentally caused. The findings, Hoover writes, are consistent with the literature behind this consensus, including studies of certain cancers among immigrant populations that come to match rates in the new homeland after several generations. Nonetheless, the discovery over the last 15 years of the genetic mechanisms underlying cancer has overshadowed environmental explanations in the minds of researchers, doctors, policymakers and the public, according to Hoover.

For cancer researchers, the most intriguing implication is that “there must be major gaps in our understanding of the genetic basis of colorectal, breast and prostate cancer.” According to the authors, who were led by Paul Lichtenstein of the Karolinska Institute, Stockholm, the frequency of known high-risk mutations is insufficient to account for observed rates of these cancers in the study. Hoover adds that the nature/nurture debate obscures the fact that “. . .genes and environment interact to produce a risk greater than the sum of their independent effects,” which can be reduced by advances in either area. For health-care professionals and individuals who wish to take charge of their health, the message is an optimistic one: genetics is not destiny.

-David Holtzman


 

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