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An Idea from Ancient Chinese Medicine (c) 2002 Brewer Science
Library, All rights reserved by Christina L. White
Right at the top of this dream treatment would be a product that is effective at destroying cancer cells without causing collateral damage to healthy cells. Yes, a nice non-toxic treatment that avoids all those nasty side effects that cause you to purchase a wig and put barf-bags on your weekly shopping list. And quick. Yes, a nice non-toxic treatment that is quick to get results; that's what I want. No fooling around; quickly eradicate the tumor or at least bring on a long-term remission. Next in line would be ease of use. Open a little bottle once or twice a day and swallow a pill or two in the privacy and comfort of one's home, at the kitchen table or maybe even stretched out in the recliner, reading the paper. I have already included non-toxic, quick acting and easy to use. I'm also going to dream it is inexpensive; so inexpensive that even the poor people of the world might be able to afford it. And of course, it must be available, right now. Since it's my dream of an ideal treatment, I'm going to go all the way and make sure it is so basic that it works with just about every kind of cancer cell, cutting through all those confusing differences. Although it might appear that I have been listening too long to the uplifting Rodgers and Hammerstein's melody To Dream the Impossible Dream, research from the University of Washington's bioengineering labs of Professors Lai and Singh may have discovered how a compound from the Chinese herb sweet wormwood (qinghao in Chinese) can fulfill all these requirements. Herbal Recipe from a Nobleman's Tomb Dr. Lai recently came across a book in his university's East Asia Library, The Cultural Relics Unearthed from the Han Tombs at Mawangdui, by Fu Juyou and Chen Songchang (Hunan Publishing House, FOLIO DA 793 M247 F8 1992) that details the fascinating story of this archeological project. Originally believed to be a tomb of a prince of the Han Dynasty, it was later determined to be the tomb of the Han nobleman, "Marquis of Dai", the Chancellor of Changsha, the district where the tombs are located. The tomb contained the nobleman and his wife, who were in their 50's and their son, who was in his 30's. The ancient preservation techniques were so effective that the tissues of the woman's body still demonstrated some elasticity. In the tomb they uncovered a silk scroll labeled "Medical Treatments for 52 Diseases" that contains 283 medical treatments, including herbal recipes. This silk scroll document is now the oldest existing text on Chinese medicine. One of the recipes describes soaking the leaves and branches of the artemisia herb in water overnight and then drinking the water as a treatment for malaria. In 1972 the active compound from wormwood was determined to be artemisinin (quinghaosu). Concentrated dosages of the active compound either in the form of artemisinin or several other derivatives have been used successfully since its discovery to treat malaria even when it has become resistant to traditional antimalarial drugs. Malaria is still a serious disease in tropical areas of the world with a yearly death toll of 1.5 - 2.7 million, so this rediscovery of wormwood's usefulness has and will continue to save many lives. The malaria parasite enters the red blood cells and sequesters iron. The mechanism of action of artemisinin in "zapping" the malaria parasite is through the affinity of artemisinin to iron. The artemisinin compound contains two oxygen atoms hooked together in what is termed an endoperoxide linkage. In the presence of free iron this linkage breaks down, forming very reactive free radicals that cause rapid and extensive damage and death to the parasite. From Malaria Parasite to Cancer Cells During a phone conversation in 1994, Dr. Lai asked a colleague who had just returned from a malaria seminar what was new in the field. His colleague told him, "Well, there is a new antimalarial called artemisinin. Come over to my office and I'll give you a paper on it." Dr. Lai went over to his office, took the paper, and started reading it on his way back to his own office. Suddenly, the idea of using artemisinin to selectively kill cancer cells "jumped into his mind", as he says. Dr. Lai had made the simple but profound connection to the known fact that all cancer cells sequester iron just as the malaria parasite does. In order to sequester iron needed for their rapid cell division, cancer cells also have higher percentages of receptors that transport iron (called transferrin receptors) into the cells. Dr. Lai was aware of the high concentration of transferrin receptors in cancer cells because, at that same time, he was doing research trying to attach small minute magnetic beads to transferrin receptors on cancer cells. They could then be shaken with an oscillating magnetic field. The idea was that with enough shaking, the cancer cell would break apart. He called this the 'shake and break'. With this method, he found he could only kill about 1/3 of the cells in 8 hours. Breast cancer cells have five to fifteen times as many of these iron-receptors as normal breast cells, and an elevated level of iron is a common finding in breast cancer tissue as well as in other cancer cells. Leukemia cells have the highest concentration of iron, up to 1000 times more iron than normal cells. Dr. Lai wondered if artemisinin compounds would demonstrate the same free radical damaging cascade in cancer cells as they do to the malaria parasite. Starting in 1994 and later with research funding from the Breast Cancer Fund in San Francisco, Dr. Lai and his colleague, Dr. Narendra Singh, Ph.D., M.D., initiated some test tube studies with cancer cells. Meanwhile, the University of Washington patented his potential cancer treatment. Test Tube Results with Artemisinin These results become even more potentially important because the breast cancer cells used in the study were radiation resistant, a difficult situation to overcome. An earlier study with human leukemia cells demonstrated 100% cancer cell destruction in half the time (8 hours) as the breast cancer cells, probably due to the rapid cell division and higher iron concentration of leukemia cells. ("Selective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin," Cancer Letters 91 {1995} 41-46) These results were encouraging, but often test tube results do not carry over into animal testing, which was the next step. The Rat Study Normally, at this point in research, the animal studies would be continued for several years with toxicity studies and further studies proving the efficacy of the protocol. Then small human studies would be started, again determining the toxicity levels and efficacy. This whole process takes years to complete before the general public would have access to this new treatment. The development of this protocol has taken a different turn though, mainly due to the fact that artemisinin and its derivatives have been available and in use for 30 years, and have generally been considered safe and non-toxic (read toxicity information below). The herb itself has been used by the Chinese for many centuries. Dr. Lai has recognized a new use for a known substance. Concern about Iron Supplementation Dr. Singh says that cancers that have developed (not been implanted) in biological tissue usually have sequestered enough iron so that it is generally not necessary to take supplemental iron for the artemisinin to be effective. Dr. Singh started treating several cancer patients in India without an iron supplement and had observed a positive response. Once physicians realized they did not have to give their patients iron to potentiate the artemisinin, several physicians started their terminal cancer patients on low doses. As word traveled through the cancer network, many patients who had exhausted all other options also initiated self-treatment with artemisinin. However, the possibility that concurrent intake of an iron supplement may enhance the effectiveness of artemisinin has not been further explored. Early Success with Canine
Osteosarcoma Stories of Success The results of a current clinical trial with patients having a variety of cancers have not been published yet, although word has it that the results were "good". We will not know how good until the full report comes out. If they are half as good as some of the following anecdotal stories we will have some interesting reports. Prostate Cancer Stories Another man with a PSA of 4 was able to drop it down to 2 in six weeks. He was then feeling so well he was able to go on a trip to South America and was able to ride on a bicycle again. Another man was able to lower his PSA from 7.8 to 1.9 in three weeks. A doctor was able to lower his PSA from 3 down to .45 in six weeks. Pancreatic Cancer Brain Tumors Tongue Tumor Breast Cancer Two outstanding cases of breast cancer success were written up in Dr. Robert Rowen's article, "Chinese Herb Cures Cancer," in the May 2002 Second Opinion. One was a 47-year-old woman with stage-IV breast cancer with metastases to her spine, causing significant pain and limping. Various alternative therapies gave her some symptom relief, but no change was registered on her CT scan until a course of artemisinin was instituted. The other breast cancer case he writes of is a large, oozing cancer that cleared up in a month on artemisinin derivatives. Lymphoma Types of Cancers Responding Further testing by other researchers with the addition of iron was able to overcome the resistance of drug-resistant small-cell lung carcinoma cells to artemisinin. ("Transferrin overcomes drug resistance to artemisinin in human small-cell lung carcinoma cells," Cancer Letters 179 {2002} 151-156) These test tube results are particularly exciting for brain cancers such as glioblastoma which have limited options. Renal carcinoma is particularly resistant to chemotherapy, so any additional possibility for control of this cancer is very welcome (read page 5, recounting Dr. Bihari's success using naltrexone with renal cancer). As stated previously, it is unusual that these test tube screening results would be tested out so soon in human subjects, especially as self-administered protocols. Due to the availability of artemisinin derivatives, though, that is exactly what has happened. To the scientific community, though, this may seem like putting the cart before the horse, but people with few options left to control their cancers are trying these derivatives in increasing numbers. So far, anecdotal reports that Dr. Singh has received have shown these derivatives provide some degree of cancer growth control, and if not remission, at least stabilization, in every type of cancer tried. Artemisinin and Derivatives There are other forms of the herb wormwood such as Artemisia absinthium (absinth sagewort or common wormwood) but they do not contain the active artemisinin compound. Even subspecies of Artemesia annua may contain different concentrations of artemisinin. The subspecia that gives the highest yield (~0.4%) is found in southwestern China and Vietnam. Various analogs of artemisinin have been developed and targeted towards treating malaria and the research on their absorption, stability and toxicity have been based on dosages and forms for this illness. New derivatives may be developed that may prove to be more efficacious for use against cancer cells. Several semi-synthetic derivatives of artemisinin have been developed in efforts to increase absorption, stability, and reduce toxicity. Although there are several other derivatives available, only the three forms that are presently being used by physicians will be discussed: artemisinin, artesunate and artemether. All three of the forms are broken down at various rates in the body into several metabolites, the principle one being dihydroartemisinin (DHA). All three forms are absorbed fairly quickly after oral intake, but each reaches a peak concentration and has effects that last different lengths of time. All three forms will go through the blood brain barrier to some degree, but the fat-soluble form has superior absorption into the brain. [Note: While reviewing some clinical studies on absorption of the various forms it quickly became apparent that the figures for absorption and the length of time the compounds are active in the blood stream vary considerably depending upon which literature is read. Sources are provided for the reader to be able to review the various statements.] Artemisinin is the active natural extract from the herb. It is not at all water-soluble and has poorer absorption than some other forms. It is quickly absorbed and reaches its peak concentration in the blood within 40 minutes. This form is broken down very quickly into its metabolites in the liver and excreted somewhat quickly, but still has some metabolic effects for as long as four hours. Human studies have shown this form to have a somewhat poor and erratic absorption, although it is the preferred form of some doctors. (see: www.Subud-health.org/page37-malariaindepth.html) Artemisinin is often given in a suppository form with children with malaria, which extends its activity before being metabolized, although rectal absorption of this compound is still somewhat poor. In suppository form it is first dissolved in fatty substances in the body or proteins and then absorbed into the body. Artemisinin is the form that is being marketed through herbal sources. Unfortunately, some of the herbal sources that have been tested have been found to have very low activity, only 5% to 10%. A 500 mg capsule that has only 5% to 10% activity will only provide 25 to 50 mg of active compound, which may be too low to obtain any results. A 100 mg capsule with 100% activity will be far more effective. Artesunate is a semi-synthetic form that is more water-soluble. This form tends to break down easily when being stored in hot climates, which is certainly a consideration for treating malaria. All the artemisinin compounds are light-sensitive; they decompose when exposed to light. One study found that when the pH (acid or alkaline state) of the stomach was more acid the rate of conversion of oral artesunate into its metabolite dihydroartemisinin was increased. This study indicated that some portion of the DHA that is formed within minutes in an acidic stomach environment is absorbed directly. The remaining amount of the parent compound artesunate that makes it to the blood stream will be converted to DHA and other metabolites more slowly in the more alkaline environment of the blood plasma. (see: study at: www.biomedcentral.com/1471-2210/1/12) One study reported that the absorption of artesunate is about 61%, and it has the shortest activity period in the body of the three forms. Some sources claim that artesunate is the most active form, but this has not been proven. Artemether is a semi-synthetic, more fat-soluble form that is the longest lasting in the blood stream. Due to the fat-soluble nature of this compound, it passes more readily through the blood brain barrier. It is also metabolized fairly rapidly to dihydroartemisinin (DHA), and blood tests show that after 6 hours the DHA metabolite has higher plasma concentrations than the parent compound artemether. (see:: www.arenco.be/docu11.htm) Dr. Lai speculates that longer acting compounds such as artemether may be better for cancer treatment. Taking the drug two times a day, 12 hours apart, keeps some in the blood stream all the time. He points out that artemisinin derivatives were originally developed to treat malaria. The malaria parasite is cyclical and the dosing schedules that were developed to blast the parasites are different than what is needed for controlling the cancer cell. The cancer cells in a tumor do not divide all at the same time; therefore he believes it is best to have some of the compound in the blood stream for longer periods of time. Various Oral Dosages Used Some people have used higher dosages to obtain their results. The woman with a stage-IV breast cancer who was back to work in four months, used 3 to 4 mg/kg of body weight as her daily dosage for a short time. The woman in Africa with the tongue tumor also used a higher amount for a week. Higher dosages may be neurotoxic after long-term use or may cause heart problems (read toxicity info below). Dr. Singh has suggested that a person of 65 kg (145 lb.) might take a combination of a 100 mg capsule of artemisinin, a 60 mg capsule of artesunate and a 40 mg capsule of artemether once a day at bedtime with a glass of milk. He also writes that the correct dosage for a specific person needs to be determined on an individual basis. Although Dr. Singh personally believes that taking all three forms of artemisinin at the same time once a day is the most effective treatment protocol, at present there is no substantiating research to verify this viewpoint. As mentioned above, Dr. Lai believes it is preferable to use only the long-lasting form of artemether and take it twice a day. It can be stated that people have obtained significant results using various forms and various dosages, and that the final determination on how these derivatives are most effective has not been determined yet. On an Empty Stomach Dr. Singh has suggested taking it with a glass of milk and Dr. Rowen in his article says that he has his patients take it with cod liver oil and conjugated linoleic acid. The artemether form is fat-soluble and the artesunate is partly fat-soluble, so taking it with fatty acids will probably assist its absorption. Intestinal Absorption &
Resistance Grapefruit juice contains antioxidants that may slow down the free radical action of the artemisinin compounds in the cancer cell. Dr. Lai suggests just taking more derivatives rather than relying on the unknown action of grapefruit juice. Piperine is a compound from black pepper that has been added to many supplements to increase their absorption. It is not known at this time if simultaneous consumption of supplements of piperine would increase the absorption of artemisinin derivatives. Decreasing absorption of artemisinin derivatives may be a problem for the longer-term use required for treatment of cancer. In treating malaria the artemisinin derivatives are given for a short four or five day course. In these short treatments no absorption resistance has been observed to occur. Recent information has come to light that indicates that the intestine builds up resistance to absorbing oral artemisinin compounds very quickly, within several days. Resistance is demonstrated by a drop to >30% of the original rate of absorption. Research indicates that this resistance can be overcome very quickly by discontinuing use of the artemisinin compounds for several days to a week; when resumed, their absorption will be at the previous higher level. (Ashton, et al., Artemisinin pharmacokinetics is time-dependent during repeated oral administration in healthy male adults, Drug Metabolism and Disposition 26 {1998} 25-27.) Dr. Lai pointed out that this intestinal resistance and subsequent lowered absorption rate may be the basis of the plateau that many people reach on these compounds. After an initial quick response, many people seem to stabilize without a complete remission. Suppository Usage Utilization of suppositories might become one way of overcoming the newly recognized intestinal absorption difficulties that develop rather quickly to oral use. Physicians may find that it is beneficial to have patients take a "drug holiday" from the oral form and switch to the suppository form. Perhaps repeated cycling of the oral doses with the suppositories will keep the intestinal resistance from becoming established. Physicians who try various cyclical dosing schedules are encouraged to contact the library with their results. Intramuscular Injection
Application Dr. Singh has developed an instruction page for doctors considering intramuscular artesunate injections. This information can be faxed to physicians requesting it. Cancer Treatment Paradox: NO
ANTIOXIDANTS Supplemental antioxidants may be contraindicated with the use of artemisinin though. The nature of the action of artemisinin compounds in the body is the creation of free radicals through interaction with iron in the cancer cell. Anything that protects against that free radical damage may be counterproductive to the effectiveness of the action of the artemisinin derivatives. Future reports from physicians may clarify this area of concern as to which kinds of nutritional supplements can be taken at the same times as these derivatives. Toxicity Potential Artemether may be the most neurotoxic form because it passes through the blood brain barrier more effectively. Animal research has shown neurotoxic results with massive doses (150 mg/kg/day versus the 1 -2 mg/kg/day used for humans with cancer). The neurotoxic results were increased when the artemether was given as pellets coated in oil, providing a fairly constant intake. This study indicated that oral administration of artemether once a day was relatively safe whereas a constant oral intake might carry a greater potential for neurotoxicity. (www.mahidol.ac.th/abstracts/annual2000/0299.htm) These dosages used in animals to create toxicity would be equivalent to 9,750 mg in humans for a 145 lb. human, far beyond what is actually being used with cancer patients. However, intramuscular artemether has higher neurotoxicity than oral dosing. Neurotoxicity is seen after repeated intramuscular administration of artemether at relatively high doses (20 mg/kg/day for 8 days), whereas no effect was observed after oral administration, even at higher dosages. (Classen et al. Differential effects of orally versus parenterally administered qinghaosu derivative artemether in dogs. Exp. Toxic. Pathol. 51 {1999} 507-516.) SUMMARY: Drs. Lai and Singh of the University of Washington may be changing the face of cancer therapy with the results of their research studies with derivatives of the Chinese herb artemesia. Cancer patients eagerly await further word on this potential breakthrough treatment for cancer. EDITOR'S NOTE: I deeply appreciate all the time, explanation and input that Dr. Henry Lai contributed to make this article a more complete overview of the development and present state of research on artemisinin as a possible treatment for cancer. Professor Henry Lai, Ph.D. Professor Narendra Singh, Ph.D.,
M.D. Sources of Artemisinin Compounds (Dr.
Lai): The next issue will discuss more results from the use of artemisinin compounds with cancer patients. Invitation to Participate in the ARTEMISININ
RESULTS SURVEY Though the collection and collation of informal results in an ongoing survey must not be misconstrued as a specific recommendation for treatment, it still can serve as a valuable and interesting source of anecdotal information for both doctors and patients alike. People who are planning to take artemisinin compounds should contact the library to request a survey questionnaire. The form will be faxed or e-mailed to them so they may participate in the survey. All the contact information (names, addresses, etc.) will be kept private and will not be given out to any other organization or company for any purpose. Requests for more forms or other information about this survey can be e-mailed to: ARTsurvey@mwt.net PH: (608) 647-6513 This article was originally published in the Summer 2002 issue of New Horizons newsletter which is published quarterly by the Brewer Science Library. Photocopying or reproduction is strictly prohibited without permission from the publisher. DISCLAIMER: The author of this article as well as the publisher offer the contained information only for educational purposes. It is not intended to be used as a means to diagnose, prescribe, or treat any health condition. The information contained in this article is not intended to be used for self-treatment or to replace consultation with a qualified health care provider. The Brewer Science Library assumes no responsibility for the implementation by anyone of any of the information contained in this newsletter.
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