Journal of Literature Pharmacy Sciences

Güncel Tedavi Yaklaşımlarından Olan Antikor İlaç Konjugatlarında Amatoksin Konjugatlarının Kullanımı: Sistematik Derleme
Use of Amatoxin Conjugates in Antibody Drug Conjugates, One of the Current Treatment Approaches: Systematic Review
Hande YÜCEa, Songül ÜNÜVARa
aİnönü Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Malatya, Türkiye
J Lit Pharm Sci. 2022;11(2):170-6
doi: 10.5336/pharmsci.2021-86316
Article Language: TR
Full Text
ÖZET
 Geleneksel kanser kemoterapisinde kullanılan ajanlar düşük terapötik indekse sahiptirler. Bu nedenle monoklonal bir antikor, bağlayıcı bir molekül ve sitotoksik bir ajandan oluşan immünokonjugatlar olan antikor-ilaç konjugatları (AİK) geliştirilmiştir. Tümör hücrelerinde bulunan çeşitli hedef moleküllere yönelik geliştirilmiş olan bu konjugatlar, son yıllarda kanser tedavisinde kullanılmaya başlanmıştır. Kemoterapide uygulanan geleneksel tedavi yöntemlerine kıyasla bu ajanlar, yüksek düzeyde seçiciliğe ve düşük yan etki profiline sahiptirler. Bu özellikleri, standart tedaviler içinde yer almalarını sağlamıştır. Yeni geliştirilen bu konjugatlar ile ilacın doğrudan kanser hücreleri üzerine hedeflenmesi amaçlanmaktadır. Buna bağlı olarak da sistemik toksisitenin azaltılması ve tedavi etkinliğinin artırılması hedeflenmektedir. Son yıllarda farklı sitotoksik ajanlar AİK'lerinde kullanılmışlardır. Sitotoksik ajanlar; tübülin hasarı yapanlar ve DNA hasarı yapanlar olmak üzere 2 ayrı mekanizmaya sahiptirler. Amanitin bazlı AİK'leri ise RNA polimeraz II üzerinde inhibitör etki göstermektedirler. Bu şekilde çok düşük konsantrasyonlarda bile DNA transkripsiyonunu inhibe etmektedirler. Bu konjugatlar, tümör mikro-ortamı ile dinamik etkileşime girerek, terapötik etkinlikte artış sağlarlar. Amanitin bazlı konjugatların geliştirilmesi oldukça yeni bir yaklaşımdır. Amanitin, çoklu ilaç direnci gösteren tümör hücreleri üzerinde düşük konsantrasyonlarda bile yüksek sitotoksik etki gösterir. AİK'lerinin tasarlanması, bireyselleştirilmiş kanser tedavilerinin geliştirilmesine önemli katkı sağlayacaktır. Son yıllarda amanitin toksini, AİK'lerinin yapısında yer alan ajanlardan biridir. Mikrogram düzeylerde bile pek çok tümörün mikro çevresinde sitotoksik etki gösterir. Bu derlemede amatoksin konjugatları ile ilgili güncel bilgilere yer verilmiştir.

Anahtar Kelimeler: Amatoksin; antikor-ilaç konjugatları; kemoterapi; monoklonal antikorlar
ABSTRACT
 Agents used in conventional cancer chemotherapy have a low therapeutic index. Therefore, antibody-drug conjugates (ADCs), which are immunoconjugates composed of a monoclonal antibody, a binding molecule, and a cytotoxic agent, have been developed. These conjugates, which have been developed for various target molecules in tumor cells, have been used in cancer treatment in recent years. Compared to conventional treatment methods used in chemotherapy, these agents have high selectivity and a low side-effect profile. These features have enabled them to be included in standard treatments. With these newly developed conjugates, it is aimed to target the drug directly on cancer cells. Accordingly, it is aimed to reduce systemic toxicity and increase treatment efficiency. In recent years, different cytotoxic agents have been used in ADCs. Cytotoxic agents; have two separate mechanisms: those that cause tubulin damage and those that do DNA damage. Amanitin-based ADCs show an inhibitory effect on RNA polymerase II. In this way, they inhibit DNA transcription even at very low concentrations. These conjugates interact dynamically with the tumor microenvironment, resulting in increased therapeutic efficacy. The development of amanitin-based conjugates is a fairly new approach. Amanitin exerts a high cytotoxic effect on multidrug resistant tumor cells even at low concentrations. Designing ADCs will make a significant contribution to the development of individualized cancer treatments. In recent years, amanitin toxin is one of the agents involved in the structure of ADCs. Even at microgram levels, it has a cytotoxic effect in the microenvironment of many tumors. In this review, up-to-date information about amatoxin conjugates is given.

Keywords: Amatoxin; antibody-drug conjugates; chemotherapy; monoclonal antibodies
REFERENCES:
  1. Peters C, Brown S. Antibody-drug conjugates as novel anti-cancer chemotherapeutics. Biosci Rep. 2015;35(4):e00225. [Crossref]  [PubMed]  [PMC] 
  2. Nasiri H, Valedkarimi Z, Aghebati-Maleki L, Majidi J. Antibody-drug conjugates: Promising and efficient tools for targeted cancer therapy. J Cell Physiol. 2018;233(9):6441-57. [Crossref]  [PubMed] 
  3. Lu J, Jiang F, Lu A, Zhang G. Linkers having a crucial role in antibody-drug conjugates. Int J Mol Sci. 2016;17(4):561. [Crossref]  [PubMed]  [PMC] 
  4. Dosio F, Stella B, Cerioni S, Gastaldi D, Arpicco S. Advances in anticancer antibody-drug conjugates and immunotoxins. Recent Pat Anticancer Drug Discov. 2014;9(1):35-65. [Crossref]  [PubMed] 
  5. Vu T, Claret FX. Trastuzumab: updated mechanisms of action and resistance in breast cancer. Front Oncol. 2012;2:62. [Crossref]  [PubMed]  [PMC] 
  6. Thomas A, Teicher BA, Hassan R. Antibody-drug conjugates for cancer therapy. Lancet Oncol. 2016;17(6):254-262. [Crossref]  [PubMed] 
  7. Panowski S, Bhakta S, Raab H, Polakis P, Junutula JR. Site-specific antibody drug conjugates for cancer therapy. MAbs. 2014;6(1):34-45. [Crossref]  [PubMed]  [PMC] 
  8. Brekke OH, Sandlie I. Therapeutic antibodies for human diseases at the dawn of the twenty-first century. Nat Rev Drug Discov. 2003;2(1):52-62. Erratum in: Nat Rev Drug Discov. 2003;2(3):240. [Crossref]  [PubMed] 
  9. Mahmuda A, Bande F, Al-Zihiry KJK, Abdulhaleem N, Abd Majid R, Hamat RA, et al. Monoclonal antibodies: A review of therapeutic applications and future prospects. Trop J Pharm Res. 2017;16(3):713-22. [Crossref] 
  10. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495-7. [Crossref]  [PubMed] 
  11. Harding FA, Stickler MM, Razo J, DuBridge RB. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs. 2010;2(3):256-65. [Crossref]  [PubMed]  [PMC] 
  12. Milstein C. The hybridoma revolution: an offshoot of basic research. Bioessays. 1999;21(11):966-73. [Crossref]  [PubMed] 
  13. Tsuchikama K, An Z. Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell. 2018;9(1):33-46. [Crossref]  [PubMed]  [PMC] 
  14. Laguzza BC, Nichols CL, Briggs SL, Cullinan GJ, Johnson DA, Starling JJ, et al. New antitumor monoclonal antibody-vinca conjugates LY203725 and related compounds: design, preparation, and representative in vivo activity. J Med Chem. 1989;32(3):548-55. [Crossref]  [PubMed] 
  15. Garnett MC. Targeted drug conjugates: principles and progress. Adv Drug Deliv Rev. 2001;53(2):171-216. [Crossref]  [PubMed] 
  16. Jain N, Smith SW, Ghone S, Tomczuk B. Current ADC linker chemistry. Pharm Res. 2015;32(11):3526-40. [Crossref]  [PubMed]  [PMC] 
  17. Gondi CS, Rao JS. Cathepsin B as a cancer target. Expert Opin Ther Targets. 2013;17(3):281-91. [Crossref]  [PubMed]  [PMC] 
  18. Su Z, Xiao D, Xie F, Liu L, Wang Y, Fan S, et al. Antibody-drug conjugates: Recent advances in linker chemistry. Acta Pharm Sin B. 2021;11(12):3889-3907. [Crossref]  [PubMed]  [PMC] 
  19. Nolting B. Linker technologies for antibody-drug conjugates. Methods Mol Biol. 2013;1045:71-100. [Crossref]  [PubMed] 
  20. Mills BJ, Lang CA. Differential distribution of free and bound glutathione and cyst(e)ine in human blood. Biochem Pharmacol. 1996;52(3):401-6. [Crossref]  [PubMed] 
  21. Pahl A, Lutz C, Hechler T. Amanitins and their development as a payload for antibody-drug conjugates. Drug Discov Today Technol. 2018;30:85-9. [Crossref]  [PubMed] 
  22. Sapra P, Hooper AT, O'Donnell CJ, Gerber HP. Investigational antibody drug conjugates for solid tumors. Expert Opin Investig Drugs. 2011;20(8):1131-49. [Crossref]  [PubMed] 
  23. Bhattacharyya B, Wolff J. Maytansine binding to the vinblastine sites of tubulin. FEBS Lett. 1977;75(1):159-62. [Crossref]  [PubMed] 
  24. Pettit GR, Kamano Y, Fujii Y, Herald CL, Inoue M, Brown P, et al. Marine animal biosynthetic constituents for cancer chemotherapy. J Nat Prod. 1981;44(4):482-5. [Crossref]  [PubMed] 
  25. Boger DL, Johnson DS. CC‐1065 and the duocarmycins: understanding their biological function through mechanistic studies. Angew Chem Int Ed Engl. 1996;35(13‐14):1438-74. [Crossref] 
  26. Zein N, Sinha AM, McGahren WJ, Ellestad GA. Calicheamicin gamma 1I: an antitumor antibiotic that cleaves double-stranded DNA site specifically. Science. 1988;240(4856):1198-201. [Crossref]  [PubMed] 
  27. Khongorzul P, Ling CJ, Khan FU, Ihsan AU, Zhang J. Antibody-drug conjugates: a comprehensive review. Mol Cancer Res. 2020;18(1):3-19. [Crossref]  [PubMed] 
  28. Huang S, van Duijnhoven SMJ, Sijts AJAM, van Elsas A. Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy. J Cancer Res Clin Oncol. 2020;146(12):3111-22. Epub 2020 Sep 28. [Crossref]  [PubMed]  [PMC] 
  29. Riley RS, June CH, Langer R, Mitchell MJ. Delivery technologies for cancer immunotherapy. Nat Rev Drug Discov. 2019;18(3):175-96. [Crossref]  [PubMed]  [PMC] 
  30. Bander NH, Czuczman MS, Younes A. Antibody-drug conjugate technology development for hematologic disorders. Clin Adv Hematol Oncol. 2012;10(8 Suppl 10):1-16. [PubMed] 
  31. FitzGerald DJ, Wayne AS, Kreitman RJ, Pastan I. Treatment of hematologic malignancies with immunotoxins and antibody-drug conjugates. Cancer Res. 2011;71(20):6300-9. [Crossref]  [PubMed]  [PMC] 
  32. Dahlgren D, Lennernäs H. Antibody-drug conjugates and targeted treatment strategies for hepatocellular carcinoma: a drug-delivery perspective. Molecules. 2020;25(12):2861. [Crossref]  [PubMed]  [PMC] 
  33. Walton JD, Hallen-Adams HE, Luo H. Ribosomal biosynthesis of the cyclic peptide toxins of Amanita mushrooms. Biopolymers. 2010;94(5):659-64. [Crossref]  [PubMed]  [PMC] 
  34. Moldenhauer G, Salnikov AV, Lüttgau S, Herr I, Anderl J, Faulstich H. Therapeutic potential of amanitin-conjugated anti-epithelial cell adhesion molecule monoclonal antibody against pancreatic carcinoma. J Natl Cancer Inst. 2012;104(8):622-34. [Crossref]  [PubMed] 
  35. Armstrong A, Eck SL. EpCAM: A new therapeutic target for an old cancer antigen. Cancer Biol Ther. 2003;2(4):320-6. [Crossref]  [PubMed] 
  36. Chaudry MA, Sales K, Ruf P, Lindhofer H, Winslet MC. EpCAM an immunotherapeutic target for gastrointestinal malignancy: current experience and future challenges. Br J Cancer. 2007;96(7):1013-9. [Crossref]  [PubMed]  [PMC] 
  37. Siegert MJ, Knittel CH, Süssmuth RD. A convergent total synthesis of the death cap toxin α-amanitin. Angew Chem Int Ed Engl. 2020;59(14):5500-504. [Crossref]  [PubMed]  [PMC] 
  38. Anderl J, Müller C, Heckl-Östreicher B, Wehr R. Abstract 3616: Highly potent antibody-amanitin conjugates cause tumor-selective apoptosis. Cancer Res. 2011;71(8_Supplement):3616. [Crossref] 
  39. Manzano A, Oca-a A. Antibody-drug conjugates: a promising novel therapy for the treatment of ovarian cancer. Cancers (Basel). 2020;12(8):2223. [Crossref]  [PubMed]  [PMC] 
  40. Li M, Liu ZS, Liu XL, Hui Q, Lu SY, Qu LL, et al. Clinical targeting recombinant immunotoxins for cancer therapy. Onco Targets Ther. 2017;10:3645-65. [Crossref]  [PubMed]  [PMC] 
  41. Singh RK, Jones RJ, Shirazi F, Hong S, Wang H, Wan J, et al. HDP-101, a novel BCMA-targeted antibody conjugated to α-amanitin, is active against myeloma with preferential efficacy against pre-clinical models of deletion 17p. Clin Lymphoma Myeloma Leuk. 2019;19(10):e152. [Crossref] 
  42. Van der Jeught K, Xu HC, Li YJ, Lu XB, Ji G. Drug resistance and new therapies in colorectal cancer. World J Gastroenterol. 2018;24(34):3834-3848. [Crossref]  [PubMed]  [PMC] 
  43. Bever CS, Barnych B, Hnasko R, Cheng LW, Stanker LH. A new conjugation method used for the development of an immunoassay for the detection of amanitin, a deadly mushroom toxin. Toxins (Basel). 2018;10(7):265. [Crossref]  [PubMed]  [PMC] 
  44. Gallo F, Korsak B, Müller C, Hechler T, Yanakieva D, Avrutina O, et al. Enhancing the pharmacokinetics and antitumor activity of an α-amanitin-based small-molecule drug conjugate via conjugation with an Fc Domain. J Med Chem. 2021;64(7):4117-29. [Crossref]  [PubMed] 
  45. Świderska KW, Szlachcic A, Opaliński Ł, Zakrzewska M, Otlewski J. FGF2 dual warhead conjugate with monomethyl auristatin E and α-amanitin displays a cytotoxic effect towards cancer cells overproducing FGF receptor 1. Int J Mol Sci. 2018;19(7):2098. [Crossref]  [PubMed]  [PMC] 
  46. Liu Y, Zhang X, Han C, Wan G, Huang X, Ivan C, et al. TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature. 2015;520(7549):697-701. Erratum in: Nature. 2021;597(7875):E6. [Crossref]  [PubMed]  [PMC] 
  47. Tai YT, Anderson KC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy. 2015;7(11):1187-99. [Crossref]  [PubMed]  [PMC] 
  48. Ko J, Breunig C, Figueroa V, Lehners V, Baumann A, Pálfi A, et al. Preclinical evaluation of hdp-101 a novel anti-BCMA antibody-Drug conjugate, in multiple myeloma Blood. 2017;130(Supplement 1):3070. [Link] 
  49. Horowitz BZ, Moss MJ. Amatoxin mushroom toxicity. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. [Link] 

.: Up To Date

.: Process List

Login

 Forgot your password?

 New Registration  

Contact

Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com