Journal of Literature Pharmacy Sciences

Kanser İlaçlarında Farmakogenetik: Geleneksel Derleme
Pharmacogenetics in Cancer Drugs: Traditional Review
Esra TEKCANa, Şengül TURALa
aOndokuz Mayıs Üniversitesi Tıp Fakültesi, Tıbbi Biyoloji ABD, Samsun, Türkiye
J Lit Pharm Sci. 2022;11(3):213-20
doi: 10.5336/pharmsci.2022-90847
Article Language: TR
Full Text
ÖZET
 Farmakogenomik, ilaç tedavisine yanıtın bireyler arası farklılık göstermesi ve bu değişken ilaç yanıtlarının altında yatan genetik mekanizmaların anlaşılmasına dayanır. Tedavide aynı ilacın aynı dozunun, bir grup hastada iyi yanıt oluşturabilirken, diğer bir grupta yeterli yanıt vermemesi, farklı bir grupta da ciddi yan etkilere ve hatta ölümlere neden olabilmesi mümkündür. Bu nedenle ilaç yanıtlarında bireyler arası farklılıklara belirgin şekilde katkıda bulunan DNA varyantlarının tanımlanması, tedavilerin etkinliğini artıracak ve ilaçların olumsuz yan etkilerinin oranını azaltacaktır. Genom dizilimi ve mutasyon analizi farmakogenomikte çok önemli araçlardır. Farmakogenomik, hem hastanın hem de tümörün genomunun araştırılmasını içerir, çünkü her ikisindeki varyasyonların kanser önleyici ilacın taşınması, dışarı akışı, alıkonması ve penetrasyonu üzerinde bir etkisi olduğu gözlemlenmiştir. İlaç yanıtının, reçete edilen ilaçların farmakokinetik ve farmakodinamik özelliklerine ve ilaç metabolize eden enzimler ve taşıyıcılardaki bireysel hasta polimorfizmlerine bağlı olduğu bilinmektedir. Bu derleme, ilaç metabolize eden enzimlerdeki polimorfizmlerin ilaç yanıtları üzerindeki etkisine odaklanmaktadır. Antikanser ilaçlar, genellikle çok dar bir terapötik indekse sahiptir; bu nedenle hastayı hayatı tehdit eden toksisite riskine sokmadan maksimum faydayı elde etmek için uygun dozların kullanılması çok önemlidir. Ancak hedef proteinleri ve ilaç metabolize eden enzimleri kodlayan genlerdeki spesifik polimorfizmlerin kalıtımı nedeniyle uygun dozun ayarlanması o kadar kolay değildir. Bu derleme, bu tür polimorfizmlerin birkaç örneğini ve bunların tedaviye yanıt üzerindeki etkisini sunmaktadır.

Anahtar Kelimeler: Farmakogenetik; polimorfizm; genetik; mutasyon
ABSTRACT
 Pharmacogenomics is based on the interindividual variation in response to drug therapy and the understanding of the genetic mechanisms underlying these variable drug responses. In the treatment, it is possible that the same dose of the same drug may cause a good response in one group of patients, while it may not respond adequately in another group, and it may cause serious side effects and even death in another group. Therefore, identifying DNA variants that significantly contribute to interindividual differences in drug responses will increase the efficacy of treatments and reduce the rate of adverse side effects of drugs. Genome sequencing and mutation analysis are very important tools in pharmacogenomics. Pharmacogenomics involves investigating the genome of both the patient and the tumor, as variations in both have been observed to have an effect on the transport, efflux, retention and penetration of the anticancer drug. It is known that drug response depends on the pharmacokinetic and pharmacodynamic properties of drugs and individual patient polymorphisms in drug metabolizing enzymes and transporters. This review considers the impact of existing polymorphisms in drug metabolizing enzymes on drug responses. Anticancer drugs often have a very narrow therapeutic index; therefore, it is very important to use appropriate doses to obtain maximum benefit without putting the patient at risk of life-threatening toxicity. However, due to the inheritance of specific polymorphisms in genes encoding target proteins and drug metabolizing enzymes, it isn't so easy to adjust the appropriate dose. This review presents several examples of such polymorphisms and their impact on treatment response.

Keywords: Pharmacogenetics; polymorphism; genetics; mutation
REFERENCES:
  1. Ahmed S, Zhou Z, Zhou J, Chen SQ. Pharmacogenomics of drug metabolizing enzymes and transporters: relevance to precision medicine. genomics proteomics Bioinformatics. 2016;14(5):298-313. [Crossref]  [PubMed]  [PMC] 
  2. Aboul-Soud MAM, Alzahrani AJ, Mahmoud A. Decoding variants in drug-metabolizing enzymes and transporters in solid tumor patients by whole-exome sequencing. Saudi J Biol Sci. 2021;28(1):628-34. [Crossref]  [PubMed]  [PMC] 
  3. Roden DM, George AL Jr. The genetic basis of variability in drug responses. Nat Rev Drug Discov. 2002;1(1):37-44. [Crossref]  [PubMed] 
  4. Meyer UA, Zanger UM, Schwab M. Omics and drug response. Annu Rev Pharmacol Toxicol. 2013;53:475-502. [Crossref]  [PubMed] 
  5. Franczyk B, Rysz J, Gluba-Brzózka A. Pharmacogenetics of drugs used in the treatment of cancers. Genes (Basel). 2022;13(2):311. [Crossref]  [PubMed]  [PMC] 
  6. Li J, Bluth MH. Pharmacogenomics of drug metabolizing enzymes and transporters: implications for cancer therapy. Pharmgenomics Pers Med. 2011;4:11-33. [Crossref]  [PubMed]  [PMC] 
  7. Ratain MJ, Plunkett WK Jr. Principles of Pharmacokinetics. In: Holland-Frei Cancer Medicine. 6th ed. Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Gansler TS, Holland JF, et al, eds. BC Decker: Hamilton (ON), Canada, 2003 [accessed on 10 November 2021]. Available from: [Link] 
  8. Amstutz U, Henricks LM, Offer SM, Barbarino J, Schellens JHM, Swen JJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther. 2018;103(2):210-6. [Crossref]  [PubMed]  [PMC] 
  9. Soong R, Shah N, Salto-Tellez M, Tai BC, Soo RA, Han HC, et al. Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy. Ann Oncol. 2008;19(5):915-9. [Crossref]  [PubMed]  [PMC] 
  10. Desilets A, McCarvill W, Aubin F, Bahig H, Ballivy O, Charpentier D, et al. Upfront DPYD genotyping and toxicity associated with fluoropyrimidine-based concurrent chemoradiotherapy for oropharyngeal carcinomas: a work in progress. Curr Oncol. 2022;29(2):497-509. [Crossref]  [PubMed]  [PMC] 
  11. Morel A, Boisdron-Celle M, Fey L, Soulie P, Craipeau MC, Traore S, et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther. 2006;5(11):2895-904. [Crossref]  [PubMed] 
  12. Lee W, Lockhart AC, Kim RB, Rothenberg ML. Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development. Oncologist. 2005;10(2):104-11. [Crossref]  [PubMed] 
  13. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343(13):905-14. [Crossref]  [PubMed] 
  14. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-41. [Crossref]  [PubMed] 
  15. Gao Y, Li W, Chen J, Wang X, Lv Y, Huang Y, et al. Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan. Acta Pharm Sin B. 2019;9(1):157-66. [Crossref]  [PubMed]  [PMC] 
  16. Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res. 2001;7(8):2182-94. [PubMed] 
  17. Wasserman E, Myara A, Lokiec F, Goldwasser F, Trivin F, Mahjoubi M, et al. Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports. Ann Oncol. 1997;8(10):1049-51. [Crossref]  [PubMed] 
  18. Wang Y, Shen L, Xu N, Wang JW, Jiao SC, Liu ZY, et al. UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil. World J Gastroenterol. 2012;18(45):6635-44. [Crossref]  [PubMed]  [PMC] 
  19. Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A. 1998;95(14):8170-4. [Crossref]  [PubMed]  [PMC] 
  20. Innocenti F, Grimsley C, Das S, Ramírez J, Cheng C, Kuttab-Boulos H, et al. Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics. 2002;12(9):725-33. [Crossref]  [PubMed] 
  21. Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004;22(8):1382-8. [Crossref]  [PubMed] 
  22. Kim TW, Innocenti F. Insights, challenges, and future directions in irinogenetics. Ther Drug Monit. 2007;29(3):265-70. [Crossref]  [PubMed] 
  23. Parte P, Kupfer D. Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin. Drug Metab Dispos. 2005;33(10):1446-52. [Crossref]  [PubMed] 
  24. Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004;310(3):1062-75. [Crossref]  [PubMed] 
  25. Crewe HK, Notley LM, Wunsch RM, Lennard MS, Gillam EM. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002;30(8):869-74. [Crossref]  [PubMed] 
  26. Mürdter TE, Schroth W, Bacchus-Gerybadze L, Winter S, Heinkele G, Simon W, et al; German Tamoxifen and AI Clinicians Group, Eichelbaum M, Schwab M, Brauch H. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma. Clin Pharmacol Ther. 2011;89(5):708-17. [Crossref]  [PubMed] 
  27. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97(1):30-9. [Crossref]  [PubMed] 
  28. Madlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW, et al. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011;89(5):718-25. [Crossref]  [PubMed]  [PMC] 
  29. Higgins MJ, Stearns V. CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010;12(1):7-15. [Crossref]  [PubMed] 
  30. Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009;302(13):1429-36. [Crossref]  [PubMed]  [PMC] 
  31. Bonanni B, Macis D, Maisonneuve P, Johansson HA, Gucciardo G, Oliviero P, et al. Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial. J Clin Oncol. 2006;24(22):3708-9; author reply 3709. [Crossref]  [PubMed] 
  32. Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005;23(36):9312-8. [Crossref]  [PubMed] 
  33. Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat. 2007;101(1):113-21. [Crossref]  [PubMed] 
  34. Zembutsu H, Nakamura S, Akashi-Tanaka S, Kuwayama T, Watanabe C, Takamaru T, et al. Significant effect of polymorphisms in CYP2D6 on response to tamoxifen therapy for breast cancer: a prospective multicenter study. Clin Cancer Res. 201;23(8):2019-26. [Crossref]  [PubMed] 
  35. Teh LK, Mohamed NI, Salleh MZ, Rohaizak M, Shahrun NS, Saladina JJ, et al. The risk of recurrence in breast cancer patients treated with tamoxifen: polymorphisms of CYP2D6 and ABCB1. AAPS J. 2012;14(1):52-9. [Crossref]  [PubMed]  [PMC] 
  36. Lei L, Wang X, Wu XD, Wang Z, Chen ZH, Zheng YB, et al. Association of CYP2D6*10 (c.100C>T) polymorphisms with clinical outcome of breast cancer after tamoxifen adjuvant endocrine therapy in Chinese population. Am J Transl Res. 2016;8(8):3585-92. [PubMed]  [PMC] 
  37. Franca R, Zudeh G, Pagarin S, Rabusin M, Lucafò M, Stocco G, et al. Pharmacogenetics of thiopurines. Cancer Drug Resist. 2019;2(2):256-70. [PubMed]  [PMC] 
  38. Otterness D, Szumlanski C, Lennard L, Klemetsdal B, Aarbakke J, Park-Hah JO, et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther. 1997;62(1):60-73. [Crossref]  [PubMed] 
  39. Innocenti F, Iyer L, Ratain MJ. Pharmacogenetics: a tool for individualizing antineoplastic therapy. Clin Pharmacokinet. 2000;39(5):315-25. [Crossref]  [PubMed] 
  40. Lennard L, Gibson BE, Nicole T, Lilleyman JS. Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia. Arch Dis Child. 1993;69(5):577-9. [Crossref]  [PubMed]  [PMC] 
  41. Evans WE, Hon YY, Bomgaars L, Coutre S, Holdsworth M, Janco R, et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol. 2001;19(8):2293-301. [Crossref]  [PubMed] 
  42. Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997;126(8):608-14. [Crossref]  [PubMed] 
  43. Maitland ML, Vasisht K, Ratain MJ. TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy? Trends Pharmacol Sci. 2006;27(8):432-7. [Crossref]  [PubMed] 
  44. Diekstra MH, Fritsch A, Kanefendt F, Swen JJ, Moes D, Sörgel F, et al. Population modeling integrating pharmacokinetics, pharmacodynamics, pharmacogenetics, and clinical outcome in patients with sunitinib-treated cancer. CPT Pharmacometrics Syst Pharmacol. 2017;6(9):604-13. [Crossref]  [PubMed]  [PMC] 
  45. Teo YL, Wee HL, Chue XP, Chau NM, Tan MH, Kanesvaran R, et al. Effect of the CYP3A5 and ABCB1 genotype on exposure, clinical response and manifestation of toxicities from sunitinib in Asian patients. Pharmacogenomics J. 2016;16(1):47-53. [Crossref]  [PubMed] 
  46. Balram C, Zhou Q, Cheung YB, Lee EJ. CYP3A5*3 and *6 single nucleotide polymorphisms in three distinct Asian populations. Eur J Clin Pharmacol. 2003;59(2):123-6. [Crossref]  [PubMed] 
  47. Numakura K, Tsuchiya N, Kagaya H, Takahashi M, Tsuruta H, Inoue T, et al. Clinical effects of single nucleotide polymorphisms on drug-related genes in Japanese metastatic renal cell carcinoma patients treated with sunitinib. Anticancer Drugs. 2017;28(1):97-103. [Crossref]  [PubMed] 
  48. Paragliola RM, Torino F, Papi G, Locantore P, Pontecorvi A, Corsello SM. Role of mitotane in adrenocortical carcinoma-review and state of the art. Eur Endocrinol. 2018;14(2):62-6. [Crossref]  [PubMed]  [PMC] 
  49. Arshad U, Taubert M, Kurlbaum M, Frechen S, Herterich S, Megerle F, et al. Enzyme autoinduction by mitotane supported by population pharmacokinetic modelling in a large cohort of adrenocortical carcinoma patients. Eur J Endocrinol. 2018;179(5):287-97. [Crossref]  [PubMed] 
  50. Hecht M, Veigure R, Couchman L, S Barker CI, Standing JF, Takkis K, et al. Utilization of data below the analytical limit of quantitation in pharmacokinetic analysis and modeling: promoting interdisciplinary debate. Bioanalysis. 2018;10(15):1229-48. [Crossref]  [PubMed] 
  51. Mornar A, Sertić M, Turk N, Nigović B, Kor?ić M. Simultaneous analysis of mitotane and its main metabolites in human blood and urine samples by SPE-HPLC technique. Biomed Chromatogr. 2012;26(11):1308-14. [Crossref]  [PubMed] 
  52. Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92(4):414-7. [Crossref]  [PubMed]  [PMC] 
  53. Nath A, Wang J, Stephanie Huang R. Pharmacogenetics and Pharmacogenomics of Targeted Therapeutics in Chronic Myeloid Leukemia. Mol Diagn Ther. 2017;21(6):621-31. [Crossref]  [PubMed]  [PMC] 
  54. Ankathil R, Zian AA, Nizam ZM, Azlan H, Baba AA. P0223 CYP3A4*18 and CYP3A5*3 gene polymorphisms and imatinib resistance in Malaysian patients with chronic myeloid leukaemia. Eur J Cancer. 2014;50(4):e71-2. [Crossref] 
  55. Filppula AM, Neuvonen M, Laitila J, Neuvonen PJ, Backman JT. Autoinhibition of CYP3A4 leads to important role of CYP2C8 in imatinib metabolism: variability in CYP2C8 activity may alter plasma concentrations and response. Drug Metab Dispos. 2013;41(1):50-9. [Crossref]  [PubMed] 
  56. Maddin N, Husin A, Gan SH, Aziz BA, Ankathil R. Impact of CYP3A4*18 and CYP3A5*3 polymorphisms on imatinib mesylate response among chronic myeloid leukemia patients in Malaysia. Oncol Ther. 2016;4(2):303-14. [Crossref]  [PubMed]  [PMC] 

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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