Artemisia annua und Artesunat in der Onkologie

ZUSAMMENFASSUNG

Artesunat ist ein klinisch etabliertes Medikament zur Malariabehandlung. Präklinische Daten weisen darauf hin, dass Artesunat und Artemisinin, die Leitsubstanz aus der chinesischen Heilpflanze Artemisia annua L., auch gegen Krebs eingesetzt werden könnten.

Im Allgemeinen wurden Artemisinin und Artesunat nach den bisher vorliegenden klinischen Befunden gut vertragen, wobei vereinzelt immer wieder auch signifikante Nebenwirkungen wie Hämatotoxizität, Hepatotoxizität oder Neurotoxizität auftraten. Auf das Vorkommen schwerer Nebenwirkungen muss auch weiterhin besonderes Augenmerk gelegt werden, insbesondere wenn Artesunat zusammen mit anderen Medikamenten verabreicht wird.

Die veterinärmedizinischen Studien zeigen, dass spontane Tiertumoren nicht nur ein interessantes Modell für die Translation präklinischer Daten in die Klinik sind, sondern dass Artesunat- und Artemisia-annua-Präparate eine neue Behandlungsoption für Haustiere mit Tumorerkrankungen darstellen könnten.

Die Wirksamkeit von Artesunat gegen verschiedene solide humane Tumoren ist bisher als eher mäßig einzustufen, wobei das Zervixkarzinom möglicherweise besser anzusprechen scheint. Insgesamt liegen noch zu wenige Daten vor, um die klinischen Ansprechraten bei verschiedenen Tumortypen zuverlässig beantworten zu können. Weitere größere klinische Phase-II- und -III-Studien sind nötig.

Abstract

Artesunate is a clinically established medicament for the treatment of malaria. Preclinical data indicates that artesunate and artemisinin, the lead substances from the Chinese medicinal plant Artemisia annua L., also have the potential of being used against cancer. Generally, artemisinin and artesunate have been well tolerated according to the clinical findings available to date, although significant side effects such as haematotoxicity, hepatotoxicity or neurotoxicity have occurred in isolated cases. Particular attention must continue to be paid to the occurrence of serious side effects, especially when artesunate is administered in combination with other medications. Veterinary studies show that spontaneous animal tumours offer an interesting model for the translation of preclinical data to the clinic. In this regard, artesunate and Artemisia annua preparations have the possibility of representing a new treatment option for pets with tumour diseases. However, the efficacy of artesunate against various solid human tumours has hitherto been classified as relatively modest; with cervical carcinoma possibly responding better. Overall, there is still insufficient data available to be able to reliably draw inferences about the clinical response rates in different tumour types. Further larger Phase II and III clinical trials are therefore required.

Key words

Chemotherapy - molecular pharmacology - natural products - rational phytotherapy - sesquiterpenoids - traditional Chinese medicine

Publication History

Article published online:
26 February 2024

• Literatur

• 1 Tu YY, Ni MY, Zhong YR. et al. Studies on the constituents of Artemisia annua L (author’s transl). Yao Xue Xue Bao 1981; 16: 366-370
• 2 Jeremić D, Jokić A, Behbud A. et al. New type of sesquiterpene lactones isolated from Artemisia annua L. Arteannuin B. Tetrahedron Lett 1973; 14: 3039-3042 DOI: 10.1016/S0040-4039(01)96314-2.
• 3 Tu YY. The constituents of young Artemisia annua . Zhong Yao Tong Bao 1985; 10: 35-36 18
• 4 Tu YY. Artemisinin – A gift from traditional Chinese medicine to the world (Nobel lecture). Angew Chem Int Ed Engl 2016; 55: 10210-10226 DOI: 10.1002/anie.201601967.
• 5 Ginsburg H, Atamna H. The redox status of malaria-infected erythrocytes: An overview with an emphasis on unresolved problems. Parasite 1994; 1: 5-13 DOI: 10.1051/parasite/1994011005.
• 6 Shenai BR, Sijwali PS, Singh A. et al. Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of Plasmodium falciparum . J Biol Chem 2000; 275: 29000-29010 DOI: 10.1074/jbc.M004459200.
• 7 O’Neill PM, Posner GH. A medicinal chemistry perspective on artemisinin and related endoperoxides. J Med Chem 2004; 47: 2945-2964 DOI: 10.1021/jm030571c.
• 8 Loo CS, Lam NS, Yu D. et al. Artemisinin and its derivatives in treating protozoan infections beyond malaria. Pharmacol Res 2017; 117: 192-217 DOI: 10.1016/j.phrs.2016.11.012.
• 9 Naß J, Efferth T. The activity of Artemisia spp. and their constituents against trypanosomiasis. Phytomedicine 2018; 47: 184-191 DOI: 10.1016/j.phymed.2018.06.002.
• 10 Pérez del Villar L, Burguillo FJ, López-Abán J. et al. Systematic review and meta-analysis of artemisinin based therapies for the treatment and prevention of schistosomiasis. PLoS One 2012; 7 (09) e45867 DOI: 10.1371/journal.pone.0045867.
• 11 Saeed MEM, Krishna S, Greten HJ. et al. Antischistosomal activity of artemisinin derivatives in vivo and in patients. Pharmacol Res 2016; 110: 216-226 DOI: 10.1016/j.phrs.2016.02.017.
• 12 Efferth T, Romero MR, Wolf DG. et al. The antiviral activities of artemisinin and artesunate. Clin Infect Dis 2008; 47: 804-811 DOI: 10.1086/591195.
• 13 Efferth T. Beyond malaria: The inhibition of viruses by artemisinin-type compounds. Biotechnol Adv 2018; 36: 1730-1737 DOI: 10.1016/j.biotechadv.2018.01.001.
• 14 Efferth T, Oesch F. The immunosuppressive activity of artemisinin-type drugs towards inflammatory and autoimmune diseases. Med Res Rev 2021; 41: 3023-3061 DOI: 10.1002/med.21842.
• 15 Wu T, Feng H, He M. et al. Efficacy of artemisinin and its derivatives in animal models of type 2 diabetes mellitus: A systematic review and meta-analysis. Pharmacol Res 2022; 175: 105994 DOI: 10.1016/j.phrs.2021.105994.
• 16 Efferth T, Rücker G, Falkenberg M. et al. Detection of apoptosis in KG-1a leukemic cells treated with investigational drugs. Arzneimittelforschung 1996; 46: 196-200
• 17 Efferth T. From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin Cancer Biol 2017; 46: 65-83 DOI: 10.1016/j.semcancer.2017.02.009.
• 18 Kwon JY, Moskwa N, Kang W. et al. Canine as a comparative and translational model for human mammary tumor. J Breast Cancer 2023; 26: 1-13 DOI: 10.4048/jbc.2023.26.e4.
• 19 Rutteman GR, Erich SA, Mol JA. et al. Safety and efficacy field study of artesunate for dogs with non-resectable tumours. Anticancer Res 2013; 33: 1819-1827
• 20 Hosoya K, Couto CG, London CA. et al. Comparison of high-dose intermittent and low-dose continuous oral artemisinin in dogs with naturally occurring tumors. J Am Anim Hosp Assoc 2014; 50: 390-395 DOI: 10.5326/JAAHA-MS-6145.
• 21 Breuer E, Efferth T. Treatment of iron-loaded veterinary sarcoma by Artemisia annua . Nat Prod Bioprospect 2014; 4: 113-118 DOI: 10.1007/s13659-014-0013-7.
• 22 Saeed MEM, Breuer E, Hegazy MF. et al. Retrospective study of small pet tumors treated with Artemisia annua and iron. Int J Oncol 2020; 56: 123-138 DOI: 10.3892/ijo.2019.4921.
• 23 Michaelsen FW, Saeed ME, Schwarzkopf J. et al. Activity of Artemisia annua and artemisinin derivatives, in prostate carcinoma. Phytomedicine 2015; 22: 1223-1231 DOI: 10.1016/j.phymed.2015.11.001.
• 24 Singh NP, Verma KB. Case report of a laryngeal squamous cell carcinoma treated with artesunate. Arch Oncol 2002; 10: 279-280 DOI: 10.2298/AOO0204279S.
• 25 Berger TG, Dieckmann D, Efferth T. et al. Artesunate in the treatment of metastatic uveal melanoma – first experiences. Oncol Rep 2005; 14: 1599-1603
• 26 Efferth T, Schöttler U, Krishna S. et al. Hepatotoxicity by combination treatment of temozolomide, artesunate and Chinese herbs in a glioblastoma multiforme patient: case report review of the literature. Arch Toxicol 2017; 91: 1833-1846 DOI: 10.1007/s00204-016-1810-z.
• 27 Uhl M, Schwab S, Efferth T. Fatal liver and bone marrow toxicity by combination treatment of dichloroacetate and artesunate in a glioblastoma multiforme patient: Case report and review of the literature. Front Oncol 2016; 6: 204 DOI: 10.3389/fonc.2016.00204.
• 28 Panossian LA, Garga NI, Pelletier D. Toxic brainstem encephalopathy after artemisinin treatment for breast cancer. Ann Neurol 2005; 58: 812-813 DOI: 10.1002/ana.20620.
• 29 White NJ, Ashley EA, Nosten F. Toxic brainstem encephalopathy after artemisinin treatment for breast cancer. Ann Neurol 2006; 59: 725-726 DOI: 10.1002/ana.20815.
• 30 von Hagens C, Walter-Sack I, Goeckenjan M. et al. Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2). Breast Cancer Res Treat 2017; 164: 359-369 DOI: 10.1007/s10549-017-4261-1.
• 31 König M, von Hagens C, Hoth S. et al. Investigation of ototoxicity of artesunate as add-on therapy in patients with metastatic or locally advanced breast cancer: New audiological results from a prospective, open, uncontrolled, monocentric phase I study. Cancer Chemother Pharmacol 2016; 77: 413-427 DOI: 10.1007/s00280-016-2960-7.
• 32 von Hagens C, Walter-Sack I, Goeckenjan M. et al. Long-term add-on therapy (compassionate use) with oral artesunate in patients with metastatic breast cancer after participating in a phase I study (ARTIC M33/2). Phytomedicine 2019; 54: 140-148 DOI: 10.1016/j.phymed.2018.09.178.
• 33 Deeken JF, Wang H, Hartley M. et al. A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies. Cancer Chemother Pharmacol 2018; 81: 587-596 DOI: 10.1007/s00280-018-3533-8.
• 34 Trimble CL, Levinson K, Maldonado L. et al. A first-in-human proof-of-concept trial of intravaginal artesunate to treat cervical intraepithelial neoplasia 2/3 (CIN2/3. Gynecol Oncol 2020; 157: 188-194 DOI: 10.1016/j.ygyno.2019.12.035.
• 35 Jansen FH, Adoubi I. et al. First study of oral Artenimol-R in advanced cervical cancer: Clinical benefit, tolerability and tumor markers. Anticancer Res 2011; 31: 4417-4422
• 36 Saeed MEM, Cives-Losada C, Efferth T. Biomarker expression profiling in cervix carcinoma biopsies unravels WT1 as a target of artesunate. Cancer Genomics Proteomics 2022; 19: 727-739 DOI: 10.21873/cgp.20355.
• 37 Zhang ZY, Yu SQ, Miao LY. et al. Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: A randomized controlled trial. Zhong Xi Yi Jie He Xue Bao 2008; 06: 134-138 DOI: 10.3736/jcim20080206.
• 38 Krishna S, Ganapathi S, Ster IC. et al. A randomised, double blind, placebo-controlled pilot study of oral artesunate therapy for colorectal cancer. EBioMedicine 2014; 2: 82-90 DOI: 10.1016/j.ebiom.2014.11.010.
• 39 Efferth T, Kaina B. Toxicity of the antimalarial artemisinin and its derivatives. Crit Rev Toxicol 2010; 40: 405-421 DOI: 10.3109/10408441003610571.
• 40 Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochem Pharmacol 2017; 139: 56-70 DOI: 10.1016/j.bcp.2017.03.019.