Determination of chemoresistance of ovarian cancer cells in vitro

Objectives: to provide a rationale for existing approaches for the evaluation of chemoresistance of ovarian cancer in vitro, to perform a comparative analysis of the methods and to assess the perspectives of their further application.

Materials and methods. For the review preparation, we analyzed articles on experimental testing of ovarian cancer resistance to chemotherapeutic agents, available at biomedical literature databases SciVerse Scopus (158), PubMed (323), Web of Science (285), RSCI (64). The review cited 37 recent publications, 12 of them being published over the past three years, and 16 articles being referred as pioneer publications on techniques previously and used today.

Results. Peculiarities of the main methods for assessing the resistance and sensitivity of a cancer to various chemotherapeutic drugs using primary cultures of tumor cells obtained from biopsy or surgical material are analyzed. Proliferative and metabolic activities as well as the level of cell death were considered as the main evaluated characteristics of tumor cells. The methodological features of the described methods are discussed, as well as the prospects for their further application.

Conclusion. Predictive detection of chemoresistance of ovarian cancer is based on testing the viability of tumor cells in the presence of a chemotherapeutic drug. The results of studies of the key mechanisms of chemoresistance development in tumor cells provide the rationale for improving in vitro testing.

1. State of oncological care in Russia in 2018. Eds.: А.D. Kaprin, V.V. Starinskiy, G.V. Petrova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMIRTS radiologii” Minzdrava Rossii, 2019. 236 p. (In Russ.).

2. Tyulyandin S.A., Kolomiets L.A., Morkhov K.Yu. et al. Practical guidelines on drug treatment of ovarian cancer, primary peritoneal cancer and fallopian tube cancer. Malignant tumors: RUSSCO practical guidelines, 2018;8:145–55. (In Russ.).

3. Markman M., Rothman R., Hakes T. et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 1991;9(3):389–93. DOI: 10.1200/JCO.1991.9.3.389.

4. Van Zyl B., Tang D., Bowden N.A. Biomarkers of platinum resistance in ovarian cancer: what can we use to improve treatment. Endocr Relat Cancer 2018;25(5):303–18. DOI: 10.1530/ERC17-0336.

5. Belitsky G.A., Kirsanov K.I., Lesovaya E.A., Yakubovskaya M.G. Prevention of therapy-related malignances in cancer survivors. Oncotarget 2019;10(22):2114–5. DOI: 10.18632/oncotarget.26781.

6. Belitskiy G.A., Kirsanov К.I., Lesovaya E.A., Yakubovskaya M.G. Drug carcinogenesis: risk factors and prevention opportunities. Uspekhi biologicheskoy khimii = Advances in Biological Chemistry 2020;60:173–226. (In Russ.).

7. Vasan N., Baselga J., Hyman D.M. A view on drug resistance in cancer. Nature 2019 575(7782):299–309. DOI: 10.1038/s41586-019-1730-1.

8. Cree I.A., Charlton P. Molecular chess? Hallmarks of anti-cancer drug resistance. BMC Cancer 2017;17(1):10. DOI: 10.1186/s12885-016-2999-1.

9. Nygren P. What is cancer chemotherapy? Acta Oncol 2001;40(2–3):166–74. DOI: 10.1080/02841860151116204.

10. Hanahan D., Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012;21(3):309–22. DOI: 10.1016/j.ccr.2012.02.022.

11. Alkema N.G., Wisman G.B., van der Zee A.G. et al. Studying platinum sensitivity and resistance in high-grade serous ovarian cancer: Different models for different questions. Drug Resist Updat 2016;24:55–69. DOI: 10.1016/j.drup.2015.11.005.

12. Schwarz R.F., Ng C.K., Cooke S.L. et al. Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis. PLoS Med 2015;12(2):e1001789. DOI: 10.1371/journal.pmed.1001789.

13. Cornelison R., Llaneza D.C., Landen C.N. Emerging therapeutics to overcome chemoresistance in epithelial ovarian cancer: a mini-review. Int J Mol Sci 2017;18(10). DOI: 10.3390/ijms18102171.

14. Scherbakov A.M., Sorokin D.V., Tatarskiy V.V. Jr et al. The phenomenon of acquired resistance to metformin in breast cancer cells: the interaction of growth pathways and estrogen receptor signaling. IUBMB Life 2016;68(4):281– 92. DOI: 10.1002/iub.1481.

15. Tikhomirova A.V. Criteria for evaluation of clinical efficacy of anticancer medicines. Vedomosti Nauchnogo tsentra expertizy sredstv meditsinskogo premineniya = The Bulletin of the Scientific Center for Expert Evaluation of Medicinal Products 2019;9(1):34–40. (In Russ.). DOI: 10.30895/1991-2919-2019-9-1-34-40.

16. Grendys E.C. Jr, Fiorica J.V., Orr J.W. Jr et al. Overview of a chemoresponse assay in ovarian cancer. Clin Transl Oncol 2014;16(9):761–9. DOI: 10.1007/s12094-014-1192-8.

17. Blom K., Nygren P., Larsson R., Andersson C.R. Predictive value of ex vivo chemosensitivity assays for individualized cancer chemotherapy: a meta-analysis. SLAS Technol 2017;22(3):306–14. DOI: 10.1177/2472630316686297.

18. Hamburger A., Salmon S.E. Primary bioassay of human myeloma stem cells. J Clin Invest 1977;60(4):846–54. DOI: 10.1172/JCI108839.

19. Kern D.H., Drogemuller C.R., Kennedy M.C. et al. Development of a miniaturized, improved nucleic acid precursor incorporation assay for chemosensitivity testing of human solid tumors. Cancer Res 1985;45(11–1): 5436–41.

20. Wilson J.K., Sargent J.M., Elgie A.W. et al. A feasibility study of the MTT assay for chemosensitivity testing in ovarian malignancy. Br J Cancer 1990;62(2):189–94. DOI: 10.1038/bjc.1990.258.

21. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65(1–2):55–63. DOI:10.1016/0022-1759(83)90303-4.

22. Sargent J.M. The use of the MTT assay to study drug resistance in fresh tumour samples. Recent Results Cancer Res 2003;161:13–25. DOI: 10.1007/978-3642-19022-3_2.

23. Andreotti P.E., Cree I.A., Kurbacher C.M. et al. Chemosensitivity testing of human tumors using a microplate adenosine triphosphate luminescence assay: clinical correlation for cisplatin resistance of ovarian carcinoma. Cancer Res 1995; 55(22):5276–82.

24. Salom E., Penalver M., Homesley H. et al. Correlation of pretreatment drug induced apoptosis in ovarian cancer cells with patient survival and clinical response. J Transl Med 2012;10:162. DOI: 10.1186/1479-5876-10-162.

25. Brower S.L., Fensterer J.E., Bush J.E. The ChemoFxa ssay: an ex vivo chemosensitivity and resistance assay for predicting patient response to cancer chemotherapy. Methods Mol Biol 2008;414:57–78. DOI: 10.1007/978-159745-339-4_6.

26. Von Hoff D.D., Kronmal R., Salmon S.E. et al. A Southwest Oncology Group study on the use of a human tumor cloning assay for predicting response in patients with ovarian cancer. Cancer 1991;67(1):20–7. DOI: 10.1002/1097-0142(19910101)67:1<20::aid-cncr2820670105>3.0.co;2-u.

27. Federico M., Alberts D.S., Garcia D.J. et al. In vitro drug testing of ovarian cancer using the human tumor colonyforming assay: comparison of in vitro response and clinical outcome. Gynecol Oncol 1994;55(3–2):S156–63. DOI: 10.1006/gyno.1994.1356.

28. Holloway R.W., Mehta R.S., Finkler N.J. et al. Association between in vitro platinum resistance in the EDR assay and clinical outcomes for ovarian cancer patients. J Gynecol Oncol 2002;87(1):8– 16. DOI: 10.1006/gyno.2002.6797.

29. Joo W.D., Lee J.Y., Kim J.H. et al. Efficacy of taxane and platinum-based chemotherapy guided by extreme drug resistance assay in patients with epithelial ovarian cancer. J Gynecol Oncol 2009;20(2):96–100. DOI: 10.3802/jgo.2009.20.2.96.

30. Loizzi V., Chan J.K., Osann K. et al. Survival outcomes in patients with recurrent ovarian cancer who were treated with chemoresistance assayguided chemotherapy. Am J Obstet Gynecol 2003;189(5):1301–7. DOI: 10.1067/s0002-9378(03)00629-x.

31. Tiersten A.D., Moon J., Smith H.O. et al. Chemotherapy resistance as a predictor of progression-free survival in ovarian cancer patients treated with neoadjuvant chemotherapy and surgical cytoreduction followed by intraperitoneal chemotherapy: a Southwest Oncology Group Study. Oncology 2009;77(6):395–9. DOI: 10.1159/000279386.

32. Xu X., Dai H., Zhao Y. et al. In vitro chemosensitivity assay of ascites in epithelial ovarian cancer. Eur J Gynaecol Oncol 2013;34(6):559–64.

33. Nakada S., Aoki D., Ohie S. et al. Chemosensitivity testing of ovarian cancer using the histoculture drug response assay: sensitivity to cisplatin and clinical response. Int J Gynecol Cancer 2005;15(3):445–52. DOI: 10.1111/j.1525-1438.2005.15307.x.

34. Jung P.S., Kim D.Y., Kim M.B. et al. Progression-free survival is accurately predicted in patients treated with chemotherapy for epithelial ovarian cancer by the histoculture drug response assay in a prospective correlative clinical trial at a single institution. Anticancer Res 2013;33(3):1029–34.

35. Cree I.A., Kurbacher C.M., Lamont A. et al. A prospective randomized controlled trial of tumour chemosensitivity assay directed chemotherapy versus physician’s choice in patients with recurrent platinumresistant ovarian cancer. Anticancer Drugs 2007;18(9):1093–101. DOI: 10.1097/CAD.0b013e3281de727e.

36. Herzog T.J., Krivak T.C., Fader A.N., Coleman R.L. Chemosensitivity testing with ChemoFX and overall survival in primary ovarian cancer. Am J Obstet Gynecol 2010;203(1):68.e1–6. DOI: 10.1016/j.ajog.2010.01.059.

37. Rutherford T., Orr J. Jr, Grendys E. Jr et al. A prospective study evaluating the clinical relevance of a chemoresponse assay for treatment of patients with persistent or recurrent ovarian cancer. Gynecol Oncol 2013;131(2):362–7. DOI: 10.1016/j.ygyno.2013.08.009.