"Artemisinin" TUMOR TIDBITS, A BIWEEKLY EMAIL NEWSLETTER FROM GULF COAST VETERINARY ONCOLOGY Number 98; May 2, 2003. ======================================================================= ANNOUNCEMENTS: Free Cancer Therapy for 4 months! Dogs without lymphoma having a hematocrit between 19% and 37% and a creatinine <1.8 may be eligible for this anemia study. The qualification examination is provided at no cost and eligible dogs may have all services provided at no charge (including any appropriate surgery, radiation, or chemotherapy) for 4 months. Call our offices in Houston (713.693.1166, Ms. Kelly Griffice) or San Antonio (210.822.1913, Ms. Waynette Wheeler) for additional information. Want a copy of our latest Oncology Handbook? A download is available at: http://www.gcvs.com/oncology/download.htm We support research! Visit our Foundation web site at: http://www.gcvs.com/gcvef/index.htm ======================================================================= THIS WEEK'S TUMOR TIDBIT: Artemisinin ======================================================================= What is Artemisinin? Artemisinin is a compound extracted from the plant Artemesia annua L. (sweet wormwood, also known as the Chinese herbal Qinghao) and is a sesquiterpene lactone. Artemesia annua has been used in China since AD 341 to treat febrile illness. In 1971, the active ingredient, artemisininin, was identified and isolated. Derivatives of artemisinin have been synthesized. These include: dihydroartemisinin (DHA), artemether, artesunate, arteether, and artelinic acid. These compounds have been packaged in different forms: tablets, capsules, suppositories and injectibles. DHA, artesuante and artelinate are relatively water-soluble, whereas the others are oil (fat) - soluble. The artemisinin molecule contains two oxygen atoms linked together in what is known as an ‘endoperoxide bridge’, which could react with an iron atom to form free radicals. Artemisinin is toxic to malaria parasites because the parasite contains a high amount iron in the form of heme molecules. Free radicals cause to macromolecular damages and kill the parasites. Artemisinin has been used as an antimalaria in more than two millions patients. Why is it indicated in cancer patients? Compared to normal cells, cancer cells sequester relatively large amount of iron mainly in the form of holotransferrin. Artemisinin has been shown to cause rapid and extensive damage and death in cancer cells and have relatively low toxicity to normal cells. Artemisinin had been analyzed for its activity against 55 cancer cell lines. It was most active against leukemia and colon cancer cell lines and active for melanomas, breast, ovarian, prostate, CNS, and renal cancer cell lines. Importantly, a comparison of artemisinin’s cytotoxicity with those of other standard cytostatic drugs showed that it was active in molar ranges comparable to those of established anti-tumor drugs. These results and known low toxicity of artemisinin and its derivatives make them a promising novel candidate for cancer chemotherapy. In one study regarding the activity of 22 drugs on leukemia CCRF-CEM cells lines, artemisinin showed both anti-leukemic activity if applied alone and modulation activity in combination with daunorubicin in multidrug-resistant (MDR) cells. Artemisinin and its derivatives have been found to inhibit the proliferation of cancer cells and increased cytotoxicity of perarubicin and doxorubicin in P-glycoprotein-overexpressing, and in MRP1-overexpressing, but not in their corresponding drug-sensitive cell lines. Is it Toxic? When artemisinin was tested with monkeys, they showed no toxicity after they received up to 292 mg/kg of artemether over 1 to 3 months. High oral doses of artemisinin can produce neurotoxicity such as gait disturbances, loss of spinal and pain response, respiratory depression, and ultimately cardiopulmonary arrest in large animals and limited and unique, selective brain stem neuronopathy in laboratory animals. Prolonged dose studies have not shown more extensive neuronal damage. It is argued that there is no reason to anticipate a particular risk of conventional regimes employing up to artemether 3-6mg/kg/d intramuscular or other regimes involving artesunate per rectum for a few days. So should we use it in veterinary medicine? Artemisinin is a novel anti-cancer drug with demonstrated results in killing cancer cells and may be beneficial in prolonging and improving the quality of life. There is no data to suggest it has anticancer effects in dogs with cancer. There have been two anecdotal reports, one in a dog with metastatic osteosarcoma and one in a dog with metastatic anal sac carcinoma. Both showed temporary reduction in tumor burden and improved quality of life. Presently there is a clinical trial evaluating a dosage of artemisinin at 100 mg per dog per day in those with metastatic osteosarcoma to the lungs (Georgetown University and Washington Cancer Institute). Toxicity data do not suggest that systemic toxicity occurs at therapeutic dosages. It is believed that the use of oral artemisinin protocol will produce clinically measurable cytotoxic effects in the tumor cells of canines with metastatic disease. Want to read more about it? Visit Holly Pharmaceuticals at: www.holleypharma.com Efferth et al, Anti-Malaria Drug is Also Active against Cancer, Int’l Journal of Oncology, 18; 767-773, 2001. Reungpatthanaphong, P et al Modulation of MDR by Artemisinin, artesunate and DHA in K562, GLC4 Resistant Cell Lines, Biology Pharmocology Bull. 25 (12) 1555-1561,2002. Efferth et al. Blood Cells, Molecules, and Diseases 28(2) Mar/Apr; 160-168, 2002. Posner, GH et al, Antimalarial, antiproliferative, and antitumor activities of Artemisinin Derived Dimers, J Medicinal Chemistry, 42(21),178-181, Oct. 1999. Woerdenbag, HJ et al. Cytotoxicity of artemisinin-related endoperoxides to EAT cells, J. Natural Products 56:(6),849-856, 1993. ======================================================================= As always, we hope this info helps and don't hesitate to call or email us Gulf Coast Veterinary Oncology! Kevin A. Hahn, DVM, PhD, Diplomate ACVIM (Oncology), drhahn@gcvs.com Janet K. Carreras, VMD, Diplomate ACVIM (Oncology), drcarreras@gcvs.com Glen K. King, DVM, MS, Diplomate ACVR (Radiology & Radiation Therapy), drking@gcvs.com Gulf Coast Veterinary Diagnostic Imaging & Oncology 1111 West Loop South, Suite 150, Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 W: www.gcvs.com ======================================================================= Copyright © 2003, Gulf Coast Veterinary Oncology