[en] Background/Aim: Artenimol-R is cytotoxic in transformed cervical cells and safety in humans is yet to be established. The present study investigates the clinical benefits, safety and the tumor marker effect of orally administered Artenimol-R in patients with advanced cervix carcinoma. Patients and Methods: Ten patients were treated with Artenimol-R for 28 days. Clinical symptoms, vaginal discharge and pain were followed-up. Adverse events were recorded. Biopsy samples were analyzed by immunohistochemistry for the expression of relevant tumor markers. Results: Artenimol-R treatment induced clinical remission with a median time for the disappearance of the symptoms being 7 days. No adverse events of grade 3 or 4 occurred. The expression of p53, Epidermal growth factor receptor (EGFR), and antigen Ki-67 as a cellular marker of proliferation, as well as the number of blood vessels stained by the CD31 antibody decreased, whereas the expression of transferrin receptor protein 1 (CD71) increased. Conclusion: The current pilot study provides evidence on the improvement of the clinical symptoms and the good tolerability of Artenimol-R in patients with advanced carcinoma of the cervix uteri. A survival trial with Artenimol- R in advanced patients is warranted.
Disciplines :
Oncology
Author, co-author :
Jansen, Frans Herwig
Adoubi, Innocent
Kouassi, Comoe J.C.
De Cnodder, Tine
JANSEN, Nicolas ; Centre Hospitalier Universitaire de Liège - CHU > Radiothérapie
Tschulakow, Alexander
Efferth, Thomas
Language :
English
Title :
First study of oral artenimol-R in advanced cervical cancer: clinical benefit, tolerability and tumor markers
Schiffman M, Castle PE, Jeronimo J, Rodriguez AC and Wacholder S: Human papillomavirus and cervical cancer. Lancet 370: 890-907, 2007. (Pubitemid 47371147)
Parkin DM, Sitas F, Chirenje M, Stein L, Abratt R and Wabinga H: Part I: Cancer in Indigenous Africans-burden, distribution, and trends. Lancet Oncol 9: 683-692, 2008. (Pubitemid 351878054)
Sitas F, Parkin DM, Chirenje M, Stein L, Abratt R and Wabinga H: Part II: Cancer in Indigenous Africans-causes and control. Lancet Oncol 9: 786-795, 2008.
Pectasides D, Kamposioras K, Papaxoinis G and Pectasides E: Chemotherapy for recurrent cervical cancer. Cancer Treat Rev 34: 603-613, 2008.
Movva S, Rodriguez L, Rias-Pulido H and Verschraegen C: Novel chemotherapy approaches for cervical cancer. Cancer 115: 3166-3180, 2009.
Stehman FB, Bundy BN, DiSaia PJ, Keys HM, Larson JE and Fowler WC: Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer 67: 2776-2285, 1991.
Chen HH, Zhou HJ and Fang X: Inhibition of human cancer cell line growth and human umbilical vein endomelial cell angiogenesis by artemisin derivates in vitro. Pharmacol Res 48: 231-236, 2003.
Disbrow GL, Baege AC, Kierpiec KA, Yuan H, Centeno JA, Thibodeaux CA, Hartmann D and Schlegel R: Dihydroartemisinin is cytotoxic to papillomavirus-expressing epithelial cells in vitro and in vivo. Cancer Res 65: 10854-10861, 2005. (Pubitemid 41713353)
Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W and White N. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 363: 9-17, 2004. (Pubitemid 38076919)
Staedke, SG, Jagannathan P, Yeka A, Bukirwa H, Banek K, Maiteki-Sebuguzi C, Clark TD, Nzarubara B, Njama-Meya D, Mpimbaza A, Rosenthal PJ, Kamya MR, Wabwire-Mangen F, Dorsey G and Talisuna AO: Monitoring antimalarial safety and tolerability in clinical trials: a case study from Uganda. Malar J 7: 107-117, 2008.
Quinn MA, Benedet JL, Odicino F, Maisonneuve P, Beller U, Creasman WT, Heintz AP, Ngan HY and Pecorelli S: Carcinoma of the cervix uteri. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 95(Supp1 1): S43-103, 2008.
Yaziji H and Gown AM: Immunohistochemical analysis of gynecologic tumors. Int J Gynecol Pathol 20: 64-78, 2001. (Pubitemid 32042158)
Efferth T, Sauerbrey A, Olbrich A, Gebhart E, Rauch P, Weber HO, Hengstler JG, Halatsch ME, Volm M, Tew KD, Ross DD and Funk JO: Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol 64: 382-394, 2003. (Pubitemid 36910002)
Efferth T, Benakis A, Romero MR, Tomicic M, Rauh R, Steinbach D, Hafer R, Stamminger T, Oesch F, Kaina B, and Marschall M. Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron. Free Radic Biol Med 37: 998-1009, 2004. (Pubitemid 39164582)
Sertel S, Eichhorn T, Sieber S, Sauer A, Weiss J, Plinkert PK and Efferth T: Factors determining sensitivity or resistance of tumor cell lines towards artesunate. Chem Biol Interact 185: 42-52, 2010.
Jansen FH and Soomro SA. Chemical instability determines the biological action of the artemisinins. Curr Med Chem 14: 3243-3259, 2007.
Efferth T, Dunstan H, Sauerbrey A, Miyachi H and Chitambar CR: The anti-malarial artesunate is also active against cancer. Int J Oncol 18: 767-773, 2001.
Michaelis M, Kleinschmidt MC, Barth S, Rothweiler F, Geiler J, Breitling R, Mayer B, Deubzer H, Witt O, Kreuter J, Doerr HW, Cinatl J and Cinatl J Jr.: Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines. Biochem Pharmacol 79: 130-136, 2010.
Hou J, Wang D, Zhang R and Wang H: Experimental therapy of hepatoma with artemisinin and its derivatives: In vitro and in vivo activity, chemosensitization, and mechanisms of action. Clin Cancer Res 14: 5519-5530, 2008.
Dell'eva R, Pfeffer U, Vene R, Anfosso L, Forlani A, Albini A and Efferth T: Inhibition of angiogenesis in vivo and growth of Kaposi's sarcoma xenograft tumors by the anti-malarial artesunate. Biochem Pharmacol 68: 2359-2366, 2004. (Pubitemid 39535108)
Huan-huan C, Li-Li Y and Shang-Bin L: Artesunate reduces chicken chorioallantoic membrane neovascularisation and exhibits antiangiogenic and apoptotic activity on human microvascular dermal endothelial cell. Cancer Lett 211: 163-173, 2004. (Pubitemid 38824630)
Soomro SA, Konkimalla VB, Langenberg T, Mahringer A, Horwedel C, Holenya P Brand A, Catin C, Flicker G, Dewerchin M, Carmeliet P, Conway EM, Jansen FH and Efferth T: Design of novel artemisinin-like derivates with cytotoxic and anti-angiogenesis properties. J Cell Mol Med 15: 1122-1135, 2011.
Anfosso L, Efferth T, Albini A and Pfeffer U: Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. Pharmacogenomics J 6: 269-278, 2006. (Pubitemid 44137954)
Efferth T, Briehl MM and Tome ME: Role of antioxidant genes for the activity of artesunate against tumor cells. Int J Oncol 23: 1231-1235, 2003.
Efferth T: Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin-from bench to bedside. Planta Med 73: 299-309, 2007.
Li PC, Lam E, Roos WP, Zdzienicka MZ, Kaina B and Efferth T: Artesunate derived from traditional Chinese medicine induces DNA damage and repair. Cancer Res 68: 4347-4351, 2008.
Kelter G, Steinbach D, Konkimalla VB, Tahara T, Taketani S, Fiebig H and Efferth T: Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunate. PLoS ONE 2: e798, 2007.
