Gemsitabin Uygulanan Prostat Kanseri Hücre Hatlarında Oxaliplatin ve Sisplatinin Kemoterapötik Etkilerinin Belirlenmesi

Öz

Ürogenital kanserler içerisinde erkeklerde görülme sıklığı açısından ilk sırada yer alan prostat kanseri, kanser ilişkili ölümler arasında ikinci sırada yer almaktadır. Mevcut araştırmalar, spesifik hasta popülasyonlarında ilave avantajlar sağlamak için platin-temelli kemoterapötikler ile hedeflenmiş tedavi kombinasyonlarına odaklanmıştır. Cerrahi veya radrasyonu takiben platin bazlı kombinasyon kemoterapisi kullanımı en fazla yararı sağlamaktadır. Bu çalışmanın amacı, platin temelli kemoterapötikler sisplatin ve oksaliplatin ile Gemsitabinin tek başına ve kombine dozlarının insan prostat kanserli hücre hatları olan DU-145 ve PC3 üzerindeki hücre proliferasyonu ve apoptotik yolaklar üzerine etkilerini belirlenmektedir. Prostat kanserli hücre hatlarında bu ilaçların tek başlarına veya kombine dozlarının, hücrelerin canlılığı üzerine olan etkileri WST-1 yöntemiyle ve CASP3, CASP8 ve CASP9 genlerinin mRNA düzeylerinde ifadelenme değişiklikleri RT-PCR ile belirlendi. Sonuç olarak, içsel ve dışsal yolakta görev alan CASP8 ve CASP9 genlerinin mRNA düzeyleri değerlendirildiğinde sisplatinin içsel yolaktan (CASP9) ve oxaliplatinin ise dışsal yolaktan (CASP8) apoptozu indüklediği tespit edildi. Bu göstermektedir ki; platin temelli kemoterapötik olan oxaliplatin ve sisplatin hedef yolakta farklı proteinler üzerinden etki etmektedir. Oxaliplatinin tek başına veya gemsitabin ile kombinasyonlarının apoptotik yolakta sisplatinden daha etkin olduğunu belirlendi.

Anahtar Kelimeler

• Gemsitabin,Kaspazlar,Oxaliplatin,Prostat kanseri,Sisplatin

The Determination of Chemotherapeutic Effects of Oxaliplatin and Cisplatin In The Prostate Cancer Cell Lines Administered Gemcitabine

Abstract

While prostate cancer takes first place in terms of prevalence among genitourinary cancers in men, it is second among cancer related deaths. Current researches are focused on combining targeted therapy with platinum-based chemotherapy for achieve additional avantages for spesific patient populations. Use of platin-based combination chemotherapy followed by surgical resection and/or radiation ensures the most benefit terapy. The aim of this study was to compare the effectiveness of platinum-based chemotherapeutics Cisplatin and Oxaliplatin used single or combination doses with Gemsitabine on apoptosis and cell proliferation of DU145 and PC3 human prostate cancer cell lines. The effects of drugs alone or combinations on cell viability were determined by WST-1 method. The mRNA expression levels of Caspase-3, Caspase-8, Caspase-9 genes were analyzed by real time polymerase chain reaction (RT-PCR). As a result, when evaluated the mRNA levels of Caspase-8 and Caspase-9 genes that play role intrinsic and extrinsic pathway, it was faund that Cisplatin induced apoptosis by intrinsic pathway, and Cisplatin induced apoptosis by extrinsic pathway. It is determined that, only Oxaliplatin or along with Gemsitabin combinations are more effective on apoptotic pathway than Sisplatin.

Keywords

• Gemsitabine,Caspases,Oxaliplatin,Prostate cancer,Cisplatin

References

1. Coşkun N. Gonadotoksisite de Asetil L- Carnitin‘in testisteki koruyucu etkisi, Yüksek Lisans Tezi, Histoloji Embriyoloji AD., Gazi Üniversitesi, Ankara, 2011.
2. Curran WJ. New chemotherapeutic agents: update of major chemoradiation trials in solid tumors. Oncology.2002; 63(2): 29-38. Daugaard G, Abildgaard U, Holstein-Rathlou NH, Bruunshuus I, Bucher D, Leyssac PP. Renal tubular function in patients treated with high-dose cisplatin. Clin Pharmacol Ther. 1988; 44 (2):164-72.
3. Desoize B, Modoulet C. Particular aspects of platinum compounds used at present in cancer treatment. Crit Rev Oncol Hematol. 2002; 42(3): 317-25. Review.
4. Di Lorenzo G, Autorino R, Giuliano M, Morelli E, Giordano A, Napodano G, Russo A, Benincasa G, D'armiento M, Altieri V, De Placido S. Phase II trial of gemcitabine, prednisone, and zoledronic acid in pretreated patients with hormone refractory prostate cancer. Urology. 2007; 69(2): 347-351.
5. Fakhrian K, Ordu AD, Haller B, Theisen J, Lordick F, Bišof V, Molls M, Geinitz H. Cisplatin- vs. oxaliplatin-based radiosensitizing chemotherapy for squamous cell carcinoma of the esophagus: a comparison of two preoperative radiochemotherapy regimens. Strahlenther Onkol. 2014; 190(11): 987-92.
6. Hamers FPT, Gispen WH, Neijt JP. Neurotoxic side-effects of cisplatin. Eur J Cancer. 1991; 27(3): 372-6.
7. Hertel LW, Boder GB, Kroin JS. Evaluation of the antitumor activity of gemcitabine 2’ 2’- diflurodeoxycytidine. Cancer Research. 1990; 50(14): 4417-4422.
8. Kamiyama Y, Mitsuzuka K, Watanabe M, Kawamorita N, Yamada S, Kaiho Y, Ito A, Nakagawa H, Arai Y. Chemotherapy with Gemcitabine and Cisplatin for Advanced Ductal Adenocarcinoma of the Prostate: Clinical Courses of Two Patients. Tohoku J Exp Med. 2015; 237(4): 317-321.

9. Kelland L. The resurgence of platinum based cancer chemotherapy. Nat Rev Cancer. 2007; 7: 573- 584 .
10. Kim YS, Sym SJ, Park SH, Park I, Hong J, Ahn HK, Park J, Cho EK, Lee WK, Chung M, Lee JH, Shin DB. A randomized phase II study of weekly docetaxel/cisplatin versus weekly docetaxel/oxaliplatin as first-line therapy for patients with advanced gastric cancer. Cancer Chemother Pharmacol. 2013; 73(1):163-169.
11. Kolomeyevskaya Nonna V, Lele Shashikant B, Miller Austin, Riebandt Grazyna C, Blum Bonnie L, Odunsi Kunle O, Frederick Peter J. Oxaliplatin is a safe alternative option for patients with recurrent gynecologic cancers after hypersensitivity reaction to Carboplatin. official journal of the International Gynecological Cancer Society. 2014; 25: 42-48.
12. Koochekpour S. Genetic and epigenetic changes in human prostate cancer. Iran Red Crescent Medical Journal. 2011; 13(2): 80-98.
13. Lee JL, Choi JH, Kim Y, Hong SW, Lee KH, Jeong IG, Song C, Hong BS, Hong JH, Ahn H. Gemcitabine–oxaliplatin plus prednisolone is active in patients with castration-resistant prostate cancer for whom docetaxel-based chemotherapy failed. British Journal of Cancer. 2014; 110: 2472-2478.
14. Li Z, Hou M, Wang H, Wang Z. A randomized study of gemcitabine plus oxaliplatin versus gemcitabine plus cisplatin as the 1st line chemotherapy for advanced non-small cell lung cancer in elderly patients. Zhongguo Fei Ai Za Zhi. 2011; 14(7): 588-92.
15. Liu Y, Chen L, He X, Fan L, Yang G, Chen X, Lin X, Du L, Li Z, Ye H, Mao Y, Zhao X, Wei Y. Enhancement of therapeutic effectiveness by combining liposomal honokiol with cisplatin in ovarian carcinoma. International Journal of Gynecological Cancer Volume. 2007; 18(4): 652–659.
16. Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, Zaniboni A, Ducreux M, Aitini E, Taieb J, Faroux R, Lepere C, De Gramont A. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005; 23(15): 3509-3516.
17. Marasco D, Messori L, Marzo T, Merlino A. Oxaliplatin vs. cisplatin: competition experiments on their binding to lysozyme. Dalton Trans. 2015; 44(22): 10392-10398. Morant R, Bernhard J, Maibach R, Borner M, Fey MF, Thurlimann B, Jacky E, Trinkler F, Bauer J, Zulian G, Hanselmann S, Hurny C. Response and palliation in a phase II trial of gemcitabine in hormone-refractory metastatic prostatic carcinoma. Ann Oncol. 2000; 11(2): 183-188.
18. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-ındependent prostate cancer. Clinical Cancer Research. 2006; 12: 1665-1671. Rentsch CA, Cecchini MG, Thalmann GN. Loss of inhibition over master pathways of bone mass regulation results in osteosclerotic bone metastases in prostate cancer. Swiss Medical Weekly. 2009; 139(15-16): 220-225.
19. Tüfekçi Ö, Güneş D, Özoğul C, Kolatan E, Altun Z, Yılmaz O, Aktaş S, Erbayraktar Z, Kırkım G, Mutafoğlu K, Soylu A, Şerbetçioğlu B, Güneri EA, Olgun N. Evaluation of the effect of acetyl L-Carnitine on experimental cisplatin nephrotoxicity. Chemotherapy. 2009; 55: 451-459.
20. Santisteban M, Pérez-Gracia Jl, Ceballos J, Vivas İ, Garcia-Foncillas J. Oxaliplatin plus gemcitabine as a salvage schedule for hormone-refractory prostate adenocarcinoma. Clin Transl Oncol. 2008; 10(6): 372-374.
21. Wang D, Lippart SJ. Cellular processing of platinum anticancer drugs, Nat Rev Drug Discov. 2005; 4: 307-320.
22. Zou Z, Zhang W, Young D, Gleave MG, Rennie P, Connell T, Connelly R, Moul J, Srivastava S, Sesterhenn I. Maspin expression profile in human prostate cancer (CaP) and in vitro induction of Masp in expression by androgen ablation. Clin Cancer Res. 2002; 8(5): 1172-1177.