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[The Sino Med Research Institute does not advocate the use of artemisinin and its derivatives to treat disease. Although it is recommended by the World Health Organization as a treatment for malaria, the U.S. Food and Drug Administration (FDA) does not currently approve the use of artemisinin and its derivatives for the treatment of any disease. Research on artemisinin and its derivatives and cancer is still in the very early stage. Human use of them should be considered experimental and taking artemisinin or its derivatives and any supplements should be approached with caution. If you are seeking treatment for any medical disease, please consult a qualified health care professional.] Artemisinin, Its Derivatives and Cancer Qingcai Zhang Sino-Med Research Institute New York 1. From Malaria to Babesia to Cancer Artemisinin is an active ingredient extracted from the traditional Chinese medicinal herb Qing Hao (Herba Artemisiae annuae), a sweet wormwood plant. In more than three decades, Artemisinin and its molecule-modified derivatives, such as artesunate, have undergone extensive basic and clinical studies for its anti-malaria effects. As a result, the World Health Organization has stated artesunate as the first line treatment for malaria. Since then, millions of malaria patients have been successfully treated with artesunate and it was also shown to be effective in cases of drug-resistant malaria. Articles are available documenting the extensive pre-clinical and clinical studies that have been done. (Bharel S, et al., 1996, Gulati A et al., 1996) Babesia is a malaria-like protozoa infection of the red blood cells and a common co-infection of Lyme disease. In Zhang Clinic, we have found artesunate to be an effective treatment for Babesiosis as well. Current research on artesunate is starting to reveal its potentials in cancer treatment. (Efferth T, et al., 2001) Currently, Zhang Clinic is using artesunate as a non-toxic adjunctive treatment for supporting the health of cancer patients. 2. Pre-Clinical Studies— Anti-Malaria, -Babesia, and -Cancer Mechanisms The mechanism of anti-malaria and babesia protozoa action of artemisinin and its derivatives is speculated to be related to the iron metabolism of protozoa. Its molecular peroxide group produces reactive oxygen atoms, which can interfere with the iron metabolism of protozoa. Iron is required for cell division as cancer cells can aggressively accumulate iron for their rapid cell reproduction. Artemisinin and its derivatives can interfere with this type of abnormal cell reproduction and promote the cell to enter apoptosis (Schaller J, 2006). Artemisinin and its derivatives have been shown to affect oxygen and carbon based free radical mechanisms. Its structure includes an endoperoxide bridge. Peroxides generate free radicals in a Fenton type reaction when exposed to unbound ferrous iron. Malaria and babesia invade and grow in erythrocytes (red blood cells), have the opportunity to accumulate excess iron, which can spill into the unbound form. Electron microscopy has confirmed the destruction of plasmodium membranes with morphology typical of free radical mechanisms. Knowing that there is a high accumulation of iron in cancer cells, researchers Henry Lai and Narenda Singh of the University of Washington became interested in the possible positive effects artemisinin may have against malignant cells. In 1995, they published a paper in Cancer Letters regarding the use of artemisinin against numerous cancer cell lines in vitro. This article has mobilized interest in artemisinin as an addition to cancer treatment. (Lai H et al., 1995). They further confirmed this theory and reported that artemisinin-tagged holotransferrin can enhance the selective cancer cell killing effects of artemisinin and were not toxic to normal cells. Lai and Singh found that after tagging artemisinin to transferrin, both iron and artemisinin would be transported into cancer cells in one package. Once inside the cell, iron is released and can readily react with the artemisinin tagged to the transferrin. This in turn, enhanced the selectivity of artemisinin’s effects on cancer cells. This was then tested on a human leukemia cell line (Molt-4) and normal human lymphocytes. It was found that the holotransferrin-tagged artemisinin was both potent and selective in killing cancer cells, and did not cause harm to normal cells. Thus, it was concluded that the 'tagged-compound' could potentially be developed into an effective chemotherapeutic agent for cancer treatment (Lai H et al., 2005). Another anti-cancer effect of artemisinin and its derivatives is the ability to promote cancer cells to enter apoptosis (programmed cell-death). Increasing the amount of iron in cancer cells could enhance this effect. Singh NP et al. reported that cancer cell lined Molt-4 cells were first incubated with 12 microM of human holotransferrin to enhance the iron supply to the cells. The cells were then pelleted and transferred to a culture media containing 200 microM of a derivative of artemisinnin, dihydroartemisinin (DHA) and then incubated. It was found that DHA treatment significantly decreased cell counts and increased the proportion of apoptosis in cancer cells compared to the controls (chi2=4.5, df=l, p<0.035). The addition of holotransferrin further decreased cell counts significantly (chi2=4.5, df=l, p<0.035) and increased apoptosis (chi2=4.5, df=1, p<0.035). No necrotic cells were observed. It was concluded that the rapid induction of apoptosis in cancer cells after treatment with DHA indicates that artemisinin and its derivatives may be effective anti-cancer agents (Singh Np et al., 2004). One of the derivatives of artemisinin, deoxyartemisitene, has been tested to have the effects to suppress 14 different types of human cancer cell lines. (Galal AM, et al., 2002) The following cancers were shown to have the highest sensitivity to these substances: leukemia, colon cancer, and melanoma. (Berger TG et al., 2005, Efferth T, et al., 2002) It has also shown suppressive effects on following cancers: breast cancer, ovarian cancer, prostate cancer, brain cancer, kidney cancer and others. (Efferth T, et al., 2006, Anfosso L, et al., 2006, Paik IH, et al., 2006, Galal AM, et al., 2002, Lee CH, et al., 2000, Singh NP, et al., 2001) Similar anti-cancer activities have also been found in other derivatives of artemisinin, such as arteether, artemether and dehydroartemisinin (Singh NP, et al., 2001). Cell cultures of drug-resistant breast cancer were found to have a high propensity of iron accumulation. When these iron-loaded cells were treated with artemisinin, 75% died within eight hours and nearly 100% died within 24 hours. In the control, normal cell cultures without heavy iron loads were not affected. (Singh NP, et al., 2001, Lai H, et al., 1995) Thus, the existence of heavy iron load seems to be a condition required for artemisinin and its derivatives to suppress cancer cells. This has been confirmed in animal studies. (Moore JC, et al., 1995) and it is believed that the main cancer suppressing mechanism of artemisinin and its derivatives is in the peroxide-oxygen spark that occurs inside the cancer cell. (Schaller J, 2006, Efferth T. et al., 2006) The current theory is that if we can increase cellular iron load by using a method such as holotransferrin then the efficacy of cancer treatment by these derivatives, especially dihydroartemisinin, can be enhanced. (Singh NP, et al., 2001) Another possible mechanism is that these substances can combine with and alter the functions of certain proteins unique to cancer cells. (Lee CH, et al., 2000) These effects work together to promote cancers cell entering apoptosis. (Singh NP, et al., 2004). Artesunate is a semi-synthetic derivative of artemisinin, and has been analyzed for its anti-cancer abilities against 55 types of cancer cell lines by the Developmental Therapeutics Program of the National Cancer Institute, USA. (Efferth et al., 2001) Artesunate demonstrated dramatic cytotoxic activities against a wide variety of cancers including drug resistant cell lines. Artesunate was shown to be most active against leukemia and colon cancer cell lines. The mean 50% growth inhibition (GI50) concentrations for them were 1.11microM and 2.13 microM respectively. Non-small cell lung cancer cell lines showed the highest mean (GI50 26.62 microM) indicating the lowest sensitivity towards artesunate. Intermediate GI50 values were obtained for melanomas, breast, ovarian, prostate, CNS, and renal cancer cell lines. Most importantly, a comparison of artesunate’s cytotoxicity with currently used cytostatic drugs showed that artesunate was active in micro molar ranges comparable to those of established anti-tumor drugs. Leukemia lines resistant to doxorubicin, vincristine, methotrexate, or hydroxyurea were tested. Remarkably, none of these drug resistant lines showed resistance to artesunate. The theorized reason for this is the absence of a tertiary amine in artesunate (required for cellular transport systems to usher the drug outside the cell), which is present in virtually all currently used chemotherapy drug agents. (Rowen R, 2002). Cancer cells are deficient in antioxidant enzyme superoxide dismutase. The manganese in mitochondria and copper zinc in cell cytoplasm are generally lower in cancer cells. Cancer cells are also grossly deficient in catalase and glutathione peroxidase, both of which degrade hydrogen peroxide. It is the deficiencies in antioxidant enzymes lead to the use of many types of common chemotherapeutics that are superoxide generators. The higher iron fluxes, especially associated with the mitosis phase of cancer cells, should render these cells more susceptible to oxidative damage via hydrogen peroxide and superoxides. Normally, the profound catalase deficiency in cancer cells is credited with creating vulnerability to oxidants. However, since all of these protective antioxidant enzymes are often deficient in transformed cancer cells, the oxidant vulnerability is dramatically enhanced due to unbound iron during cell division. This is one of the anti-cancer mechanisms of artemisinin and its derivatives (Levine SA, et al.,1985). 3. Clinical Observations Clinically, Dr. NP Singh has been following a series of cancer patients with nearly universal improvement while being treated by artemisinin or its derivatives. He believes that artemisinin will prove to be one of the most powerful therapeutic agents in cancer treatment. He emphasizes that it should be used in a professional medical settings together with complementary strategies employing detoxification, diet, immune support, and spiritual work. The Dr. Hoang has observed a 50-60% long-term remission in over 400 cancer patients utilizing artemisinin together with a comprehensive cancer strategy, and with no observed toxicity (Rowen R, 2002). In Zhang Clinic, we have been using artesunate for treating pre-cancerous conditions. Three cases of biopsy-confirmed stomach intestinal epithelium metaplasia, which is a pre-cancerous condition of stomach cancer, treated with Artemisia Capsule (contains artesunate 33.3 mg per capsule) three times a day for two months. Subsequent GI biopsies found that the metaplasia was no longer there. In several patients diagnosed with cervical dysplasia by PAP smear, Allicin Capsule and Artemesia Capsule (both used as vaginal suppository) was used for several weeks. In every case, follow-up PAP smear checks for dysplasia turned to negative. In patients with cancer diagnoses or those already finished with conventional oncology treatments, Artemisia Capsule was used as adjunctive supporting treatment. We have seen promising results in treating hepatocellular carcinoma (HCC), breast cancer, lymphoma, multimylenoma, urine bladder cancer, and oral cancers. In those patients whose major cancer lesions were treated by oncologic therapies but still had untreated lesions, the artesunate treatment was able to stabilize and shrink the smaller lesions. For those patients who had main cancer lesions removed by surgery, chemotherapy, or radiotherapy, artesunate treatment was used as a preventive measure for possible relapse and metastasis. Combining with other traditional Chinese medicine (TCM) herbal formulas were used as supportive agents to improve the patient’s survival and life quality. Since artemisinin and its derivatives, such as artesunate, have a wide anti-cancer spectrum, they have been clinically tested for treating following various common cancers. Hepatocellular Carcinoma (Liver Cancer): Our clinic has been treating many patients with viral hepatitis B and C. Patients in the advanced stages are at risk for developing HCC. We use artesunate (active ingredient of Artemisia Capsule) as the main treatment agent. In some of these patients, lesions have been treated by surgery or trans arterial chemo-embolism (TACE) and alcohol or radiofrequency ablation. When they initially came for treatment, every patient had untreated HCC lesions in their liver. After artesunate treatment, most of these lesions became stabilized and some scattered smaller lesions disappeared. In addition, we also focus treatment on restoring liver function and controlling liver inflammation. From our clinic experience, every HCC patients showed longer than expected survival time while overall life quality was improved. The following are two patient case studies: Case 1 Fran was 73 when she first visited Zhang Clinic on Dec. 14, 2000. She had been diagnosed with hepatocellular carcinoma (HCC) and hepatitis C in the de-compensated cirrhosis stage. Symptoms included light jaundice, gallstones, elevated ammonia (69.8), leukopenia (WBC 2.3), anemia, low platelets (60), mild ascites and edema, liver inflammation, and bile retention. She had severe fatigue and insomnia. A physical check also showed an enlarged spleen consistent with portal vein hypertension. In addition to the liver conditions, Fran also had type II diabetes. Following an MRI performed on Nov. 8, 2000, two lesions were found on her liver: one high in segment 8 measuring 2.9 x 3.0 cm; the other in segment 6, which was slightly exophytic, and measured 3.7 x 3.4 cm. Fran was treated at the Sloan - Kettering Institute. The treatments consisted of embolism on both lesions and alcohol ablation on the lower lesion. The higher lesion was not treated with ablation due to its location being too close to the lung. She was also physically too weak at that time to tolerate ablation treatment for both lesions. As her treatment options were limited, she came to Zhang Clinic seeking alternative methods. Our treatment goals focused on restoring her liver functions and controlling the cancer. The R-6532 Capsule, a modified version of TCM formula Kang Ai Bao (Wang HZ et al. 1997) was used along with a liver supportive protocol. After 3 months on treatment, Fran’s liver functions had improved, jaundice cleared, ascites and edema eliminated, and the ammonia levels normalized. A CAT scan performed on July 19, 2001 revealed that the size of the higher lesion had decreased to 1.1 x 1.1 cm (from 2.9 x 3.0 cm) and the lower lesion had decreased in size to 2.7 x 2.3 cm. (from 3.7 x 3.4 cm). No new lesions were detected. Thereafter, a CAT scan was done every 6 months. On Dec. 18, 2003, new lesions were discovered in segment 7 and 6. At this time, Fran’s general health and liver functions were strong enough to tolerate embolism and alcohol ablation treatments and were successfully completed. Since then, we have added artesunate (Artemisia Capsule) in her protocol to treat residual cancer cells and help prevent possible relapse. Fran is now 81 and enjoys a good life quality despite her compromised liver functions 8 years after the HCC diagnosis. Her lesions are checked every 6 months and have been stable. Case 2: Margaret was 58 she first visited Zhang Clinic. She had been diagnosed with HCC in May of 2003. Four months prior to her visit at Zhang Clinic, she underwent liver resection surgery. At the time of her diagnosis, a large tumor (8.5 cm) was found in segment 5 and 6 and one (2.2 x 1.6 cm) was found in segment 2. In addition, a few smaller lesions were found in segment 8. All lesions were found in the right lobe of the liver. The large tumor in segment 5 and 6 was removed by liver resection. Following the surgery no chemotherapy or radiotherapy was used. The lesion in segment 2 was treated by radiofrequency ablation. The small lesions in segment 8 were not treated. Blood tests showed her AFP was elevated (12) after surgery. ALT and GGT levels were normal but AST was mildly elevated. This was her status when she first visited Zhang’s Clinic. Since her cancer load was significantly reduced by surgery and radiofrequency ablation, we started herbal treatment with formula R-6532 Capsule. At the same time, a liver protective formula, Hepa F. #2 Capsule, was used to help restore her liver functions. The Cordyceps Capsule was also used to improve cellular immunity and Circulation P formula used to improve blood rheology and microcirculation. After 10 months on this protocol, most liver functions were in normal range, AFP decreased from 12 to 3.4 while AST was still slightly above normal range. On April 5, 2004, approximately one year after her surgery and seven months into herbal treatment, an MRI was conducted to compare with the one done prior to the herbal protocol on 9/17/03. The findings of this comparison read: The patient is status post resection of hepatic segments 5 and 6, cholecystectomy and radiofrequency ablation of a lesion in segment 2. A hypervasular lesion in hepatic segment 8 is stable. Other previously noted smaller lesions in right hepatic lobe are no longer seen. The lesion in segment 2 has decreased in size from 2.2x1.6 cm to 1.8x1.6 cm. At this point we added Artemisia Capsule, the main constituent being artesunate. One year later, on April 29 2005, another MRI was performed and compared with the MRI done on 10/4/04 and 4/5/04. It was found that the lesion at segment 2 was further reduced in size to 1.4x1.2 and previous hyper intense foci scattered throughout the liver were no longer seen. Margaret’s liver function tests were all within normal range. She has since had a yearly MRI check-up and the liver lesions remained stable. No new lesions were found. Liu Y, et al., and Sun WC, et al., studied to combine artemisinin and its derivatives with large carbon molecule, such as aslipophilic alkyl carbon chains, which can dramatically enhance its anti-HCC effects. By using large carbon chains, the HCC cell killing effects of these artemisinin derivatives was showed to be 200 times more effective. (Liu Y, et al. 2005, Sun WC, et al. 1992) Breast Cancer: Lai H, et al., found that in rats, chemically induced breast cancer could be prevented and treated by Artemisinin. The cancer-induced rats were fed food containing 0.02% of artemisinin for 40 weeks and found that only 43% of the rats actually developed cancer, whereas 96% of the rats in control group without artemisinin treatment developed cancer. (Lai H, et al. 2006) Singh NP, et al., treated human breast cancer cells with holotransferrin and dehydroaremisinin together and found that this combination was able to kill a type of radiation-resistant human breast cancer cells and showed no harmful effects on normal human breast cells. (Singh NP, et al. 2001) In Zhang Clinic, artesunate was used for breast cancer patients to help prevent relapse and metastasis after surgery, chemotherapy and/or radiation treatments. This method has been used for several years and our clinical observations showed that not one patient relapsed or developed metastasis so far. A case history reported by Townsend Letter for Doctors & Patients reads: “Patient D.E., a 47 year-old Alaska resident with stage IV breast cancer developed metastasis into vertebral T1 with significant pain, vertebral collapse and local neurological impairment. First seen May 2001, she received a series of IPT (insulin potentiation therapy-low dose chemotherapy), high dose vitamin C infusions, supplements, and dendritic cell vaccine, dietary management, and detoxification strategies. Most symptoms had cleared within 4 months (October 2001). In January 2002, she received artesunate intravenously (source: China), plus oral artemisinin 300 mg twice a day, which has been continued. Six months later she reported that she no longer experienced symptoms and her quality of life was dramatically improved. Her physician believes the regressed mass has now turned to scar tissue.” (Rowen R, 2002). Even in cases of widely metastatic breast cancer, these substances combined with other alternative supplements showed good results. Another case report reads: “L.L. is a woman in her 40s diagnosed with breast cancer. In addition, she experienced very painful bone metastasis cover most of the spine. She had received limited radiation therapy to reduce the pain in the thoracic spine. Thereafter, she began treatment with artemisinin and a variety of complementary strategies, including diet, detoxification and Kelly type proteolytic enzymes. The degree of pain immediately decreased and her comment after two weeks on artemisinin was: "Last week I thought I was dying, and today for the first time in months, I believe I am going to live." Four months into therapy using oral supplements, diet and detoxification strategies, a positron emission computerized tomographic (PET) scan showed no cancer activity in her spine, even in places where cancer was previously found. Upon further testing, scans did not confirm definite cancer activity anywhere else.” (Rowen R, 2002). Cervical Cancer: Since cervical cancer cells have large numbers of transferrin receptor to increase iron uptake, artemisinin and it derivatives, such as artesunate and dihyroartemisinin (DHA) showed strong suppressive effects against cervical cancer cells and did not show harmful effects on normal cervical tissue. Disbrow GL, et al., reported that when used topically in animal studies, it was found that applying dihyroartemisinin (DHA) in the cervical regions of dogs that were then exposed to HPV DHA strongly inhibited HPV induced cancer development (Disbrow GL., et al, 2005). In Zhang Clinic, artesunate and allitridii (the active ingredient of Allicin Capsule) mixtures have been used as a vaginal suppository to treat cervical dysplasia diagnosed by PAP smear. Follow up PAP smear results of all patients turned to normal within a few weeks of treatment. Leukemia and Lymphoma: Singh NP et al. reported that when artemisinin and sodium butyrate were used together, the combination dramatically enhanced artemisinin’s suppressive effects on leukemia cells. This combination did not harm normal white blood cells and lymphocytes. These two substances seemed to exhibit synergetic effects. When tested separately, artemisinin and butyrate showed suppression rates on leukemia cells of 40% and 32%, respectively. When tested as a combined treatment, 100% of the leukemia cells were killed within one day. (Singh NP, et al., 2005) In Zhang Clinic artesunate has been used as adjunctive support treatment for patients with chronic lymphocyte leukemia (CLL). This treatment has been able to help keep blood counts within the normal range. A case history from the Townsend Letter for Doctors & Patients reported: “Patient D.A. a 47 year-old mechanic who was presented with a 4.5 cm. Non-Hodgkin’s lymphoma on the right side of his head, with gaping incision from a recent biopsy, and tremendous inflammatory erythema. Artesunate, (60mg) was injected muscularly 14 consecutive days and while the patient changed his diets to high proteins/vegetables (Kelley parasympathetic type diet). At the end of two weeks, a depression appeared at the apex of the tumor. Four weeks later, the mass was completely gone, skull surface smooth, incision totally healed and erythema virtually cleared. He was tested to be free of cancer 6 months later.” (Rowen R, 2002) Melanoma and skin cancer: Berger TG., et al. reported on their observation in treating metastatic melanoma with artemisinin. The patient had metastatic melanoma and failed to respond to chemotherapy. After using artemisinin, the cancer was at first stabilized and then the metastatic lesions in the lung and spleen were later found regressed. When the report was writing, the patient is still alive four years after advanced melanoma was diagnosed. Generally speaking, the life expectancy of this type of cancer is less than a few months (Berger TG, et al., 2005). In skin cancer, artemisinin and its derivatives can be used as a topical application. Another case reported the use of artesunate DMSO solution applied topically. The skin cancer lesion was eliminated within a few days. The case report reads: “Patient F.A., an 81 year-old Californian with multiple skin cancers including one active recurrent quarter-sized lesion that had been burned 4 times previously. Topical artemisinin (artemisinin in 50% DMSO) applied twice daily caused the large lesion to disappear after 5 days and the other smaller lesions appeared to be decreasing.” (Rowen R, 2002) Glioma: The brain tumors usually not sensitive to chemotherapy so conventional treatment is mainly radiation therapy. Kim SJ et al., found that when dihyroartemisinin (DHA) was used together with the radiation, the glioma cells become more sensitive to radiation treatment. They also found that when the glioma cell culture was treated with DHA, the number of cell colonies was reduced and when radiation was given together with DHA treatment, the reduction of the colonies was more obvious. In their study, it was also found that when antioxidants were used, the effects of DHA was blocked. Therefore, during DHA treatment, free radical scavengers or antioxidants should not be used. (Kim SJ, et al, 2006) Other Cancers: Other types of cancer have also been studied by using artemisinin and its derivatives. These include stomach cancer (Sun WC, et al., 1992), small-cell lung cancer (Sadava D, et al., 2002), ovarian cancer (Chen HH, et al., 2003), oral squamous cell carcinoma (Yamachika E, et al.,2004), fibrosarcoma (Moore JC, et al., 1995), astrocytoma (Efferth T, et al., 2004), Kaposi’s sarconma (Dell’Eva R, et al., 2004), prostate cancer, and non-small cell lung cancer (NSCLC)… etc. Posner GH et al., reported that artemisinin derivatives had strong suppressive effects on prostate cancer. (Posner GH, et al., 1999, 2004). A case reported on NSCLC in Townsend Letter for Doctors & Patients reads: “Patient V.M. an 83 year old Toronto resident, healthy most of her life, now showed a non-small cell lung carcinoma in the right lower lobe, considered non-resectable due to the risk of heart failure and circulatory problems. The patient received artemisinin 500mg twice a day and Carnivora oral, via nebulizer 5cc twice a day. After 4 months, the tumor shrunk to 1x2 cm and her oncologist felt this actually represented scar tissue and declared her cancer free.” Her heart condition also improved considerably with CoQ10, 600mg daily (Rowen R, 2002). 4. Summary For more than three decades, Artemisinin and its derivatives have been used for treating malaria and millions of patients have been successfully treated. Its molecularly modified derivative artesunate had been recommended as the first-line anti-malaria treatment by the World Health Organization. Because of the similarities between babesiosis and malaria, we at Zhang Clinic have been using it for treating babesiosis, the most common co-infection of Lyme disease. Artesunate is more potent and showed less side effects compared to artemisinin. From our experience, its efficacy has proven to be greater than conventional medications in treating babesiosis. Because the anti-malaria and anti-babesia mechanism of artemisinin and its derivatives is shared by cancer cell division since 1995 researchers at the University of Washington started its anti-cancer studies. Pre-clinical and clinical studies found artemisinin and its derivatives to be potent anti-cancer substances with no obvious toxicity to normal cells in therapeutic dosages. On the cost basis it was much less expensive than most chemotherapy drugs. It has showed to be able to selectively affect cancer cells without harming normal cells, which seems to be an ideal anti-cancer treatment. Because it is non-toxic and it has very wide anti-cancer spectrum, it can be used immediately after cancer diagnosis to prepare the patient for additional oncotherapies. It can also be used after surgery, chemotherapy, or radiation treatments to help prevent relapse and metastasis. Its non-cytotoxic anti-cancer mechanism could possibly open a brand new field of anti-cancer research and made the development of non-toxic gentle and humane anti-cancer treatment possible. . References: Anfosso L., et al., Microarray expression profiles of angionenesis-related genes predict tumor cell response to artemisinins. Pharmacogenomics J. 6:269-78, 2006 Berger TG, et al., Artesunate in the treatment of metastatic uveal melanoma – first experiences, Oncol Rep. 2005; 14:1599-603 Bharel S, Gulati M, Abdin P, Srivastava S. Structure biosynthesis and functions of artemisinin. Fitoterapia Vol LXVII No 5, l996. Chen HH, et al., Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro." Pharmacol Res 48: 231-236, 2003. Dell’Eva R, et al., Inhibition of angiogenesis in vivo and growth of Kaposi’s sarcoma xenograft tumors by the anti-malaria artesunate. 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