The Use of Bevacizumab Alone and in Combination with Classical Chemotheropathics in Ishikawa Endometrial Cancer Cell Culture

Öz Purpose: The aim of our study is to determine the effects of an antiangiogenic agent (bevacizumab) in combination with or without classic chemotherapeutics on the endometrium carcinoma and use these information in our clinic practice. Materials and Methods: In vitro tests were done to determine the cytotoxic and apoptotic effects of Cisplatin, Adriablastine and Bevacizumab. Cytotoxic effect was determined by the standard MTT assay (Tetrozolium Test) and apopthosis by DAPI staining, caspase-3 on human endometrium cancer cell culture (Ishikawa). Results: The MTT assay determined that 9.6 mg/ml dose of bevacizumab caused a higher rate of decrease in cell number on Ishikawa cells compared to the highest doses of Cisplatin and Adriablastine. Therewithal, when Bevacizumab, Cisplatin, and Adriablastine were applied together for 24 hours, the number of cells decreased with an increasing dose. With the use of the triple combination with DAPI staining, it is seen that the cell silhouettes are effaced and the findings indicating apoptosis become more apparent. When bevacizumab was applied alone, the caspase 3 activity it produced was ascertained to be higher than the other two drugs individually and in combination. Caspase-3 activity was ascertained to have increased significantly as a result of the collective usage of 40 µM Cisplatin + 20 µM Adriablastine + 9.6 µgram / ml Bevacizumab, and this was found to be the highest cytotoxic activity compared to other applications. Conclusion: Preclinical studies have shown that murine antihuman monoclonal antibody against Vascular Endothelial Growth Factor (VEGF) have promising activity in many gynecologic and non-gynecologic human tumors.

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1. Marcus D, Savage A, Balog J, Kudo H, Abda J, Dina R, et al. P74 Endometrial cancer: Can the iKnife diagnose endometrial cancer? Int J Gynecol Cancer. 2019;29:A100-A101

2. Siegel RL, Miller KD, Jemal A. Cancer Statistics. 2017; 67(1): 7–30.

3. Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. The Lancet. 2016;387:1094-108.

4. Lu KH. Management of early stage endometrial cancer. Semin Oncol. 2009;36:137-44.

5. Hogberg T. Adjuvant chemotherapy in endometrial carcinoma:overview of randomized trials.Clin Oncol (R Coll Radiol).2008;20:463.

6. Aghajanian C, Filiaci V, Dizon DS, Carlson JW, Powell MA, Alvarez Secord A, et al. A Phase II Study of frontline paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer. Gynecol Oncol. 2018;150:274-81.

7. Howlader, N; Noone, AM; Krapcho, M, et al. SEER cancer statistics review, 1975-2012. National Cancer Institute. 2014.

8. Shay, Jerry & Wright, Woodring. Shay JW, Wright WEHayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol. 2000;1:72-76.

9.Delmonte A,Sessa C. Moleculer targeted agents in endometrial carcinoma:overview of randomised trials.Clin Oncol ( R Coll Radiol.) 2008; 20: 554.

10. Bates DO, Hillman NJ, Williams B et al. Regulation of microvascular permeability by vascular endothelial growth factors. J Anat. 2002; 200: 587-597.

11. Minami H, Ebi H, Tahara M et al. A phase I study an oral VEGF receptor tirozin kinaz inhibitor ZD6474 in Japanese patients with solid tumors. Proc Am Soc Clin Oncol 2003; 22: 194

12.Trarbach T, Shleucher N, Riedel U et al. Phase I/II study of the oral vascula ebdothelial growth factor (VEGF) receptor inhibitor PTK787/ZK222854 in combination with irinotecan/5-fluorouracil/leucoverin in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2003; 22:285

13.Zhuo, W., Wang, Y., Zhuo, X., Zhang, Y., Ao, X., Chen, Z., (2008), Knockdown of Snail, a novel zinc finger transcription factor, via RNA interference increases A549 cell sensitivity to cisplatin via JNK/mitochondrial pathway. Lung Cancer. 2008; 62: 8-14.

14. Caruso, F., Villa, R., Rossi, M., Pettinari, C., Paduano, F., Pennati, et al. Mitochondria are primary targets in apoptosis induces by the mixed phosphine gold species chlorotriphenylphosphine-1,3 bis(diphenylphosphino) propanegold(I) in melanoma cell lines, Biochemical Pharmacology. 2007; 73: 773-781.

15. Bruzzone M, Miglietta L, Franzone P, Gadducci A, Boccardo F. Combined treatment with chemotherapy and radiotherapy in high-risk FIGO stage III-IV endometrial cancer patients. Gynecol Oncol. 2004;93:345-352.

16. Homesley HD, Filiaci V, Gibbons SK, et al. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study. Gynecol Oncol. 2009;112:543-552.

17. Thigpen JT, Brady MF, Homesley HD, et al. Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004;22:3902-3908.

18. Sreedevi MS, Pavan KK, Neelakantan A. Carboplatin and paclitaxel: Role in the treatment of endometrial cancer Editor(s): Rama RM, Ganji PN. A Theranostic and Precision Medicine Approach for Female-Specific Cancers, Academic Press, 2021. p. 165-177.

19.Fleming GF,Fowler JM,Waggoner SE,et al.Phase 1 trial of escalating doses of paclitaxel combined with fixed doses of cisplatin and doxorubisin in advanced endometrial carcinoma and other gynecologic malignencies: a Gynecologic Oncology Group Study. J Clin Oncol. 2001;19:1021-1029.

20.Randall ME, Filiaci VL, Muss H, et al. Randomized Phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2006;24:36–44.

21. Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008; 109(1): 11–18

22.J. Tate Thigpen, Mark F. Brady, Howard D. Homesley, John Malfetano, Brent DuBeshter, Robert A. Burger, Shu Liao Phase III Trial of Doxorubicin With or Without Cisplatin in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study. Journal of Clinical Oncology. 2004;22(October 1): 3902-3908.

23.Rose PG, Ali S, Moslemi-Kebria M, Simpkins F. Paclitaxel, carboplatin, and bevacizumab in advanced and recurrent endometrial carcinoma. Int J Gynecol Cancer. 2017;27:452-58.

24.Lorusso D, Ferrandina G, Colombo N, Pignata S, Pietragalla A, Sonetto C, et al. Carboplatin-paclitaxel compared to carboplatin-paclitaxel-bevacizumab in advanced or recurrent endometrial Cancer: MITO END-2-A randomized phase II trial. Gynecol Oncol 2019;155:406-12

25. Chen, Hui, Minglin Liang, and Jie Min. Efficacy and Safety of Bevacizumab-Combined Chemotherapy for Advanced and Recurrent Endometrial Cancer: A Systematic Review and Meta-analysis. Balkan medical journal. 2021;38:7-12.