The study was aimed to determine the platinum-resistance biomarkers in patients with ovarian cancer. The expression of ABCA1 is higher in platinum-resistant cases of ovarian cancer. The most pronounced relationship exists between the values of survivin expression, local activity of nitric oxide, the expression of glutathione dependent enzymes, the content of catecholamines in erythrocytes, and the expression of ABCA1 transporter

Rybin, A.

Journal of Education Health and Sport

English

The study was aimed to determine the platinum-resistance biomarkers in patients with ovarian cancer. The expression of ABCA1 is higher in platinum-resistant cases of ovarian cancer. The most pronounced relationship exists between the values of survivin expression, local activity of nitric oxide, the expression of glutathione dependent enzymes, the content of catecholamines in erythrocytes, and the expression of ABCA1 transporte

Andriy Rybin

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 594 Rybin Andriy. Modern strategies of platinum resistance overcoming in patients with the serous ovarian cancer. Journal of Education, Health and Sport. 2018;8(11):594-599. eISNN 2391-8306. DOI http://dx.doi.org/10.5281/zenodo.2535662  http://ojs.ukw.edu.pl/index.php/johs/article/view/6453     The journal has had 7 points in Ministry of Science and Higher Education parametric evaluation. Part b item 1223 (26/01/2017). 1223 Journal of Education, Health and Sport eISSN 2391-8306 7 © The Author(s) 2018; This article is published with open access at Licensee Open Journal Systems of Kazimierz Wielki University in Bydgoszcz, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 19.11.2018. Revised: 22.11.2018. Accepted: 30.11.2018.   Modern strategies of platinum resistance overcoming in patients with the serous ovarian cancer  Andriy Rybin   Odessa National Medical University, Odessa, Ukraine  Assistant Professor, Surgical Department №4 with oncology course   Abstract The study was aimed to determine the platinum-resistance biomarkers in patients with ovarian cancer. The expression of ABCA1 is higher in platinum-resistant cases of ovarian cancer. The most pronounced relationship exists between the values of survivin expression, local activity of nitric oxide, the expression of glutathione dependent enzymes, the content of catecholamines in erythrocytes, and the expression of ABCA1 transporter Key words: ovarian cancer, platitum resistance, biomarkers  Introduction. According to the International Agency for Research on Cancer, more than 165,000 new cases of ovarian cancer are reported annually in the world and more than 100,000 women die from malignant ovarian tumors. According to mortality rates, ovarian cancer ranking 5th among the causes of death from all tumors in women. The mortality of patients with ovarian cancer in the first year after diagnosis is 35% [1, 2]. Overall five-year survival rate of patients with ovarian cancer does not exceed 35-40% [3]. These circumstances are due to the asymptomatic flow of ovarian cancerRH in the early stages, which leads to late diagnosis of the disease, when radical surgical intervention is not possible. The problem of ovarian cancer has a huge medical and social significance. According to the aggregated data of population cancer registries of European countries, one-year survival rate of  595 patients with MS is 63%, three years - 41%, five years - 35%. In the last decade in Europe, the increase in the five-year survival rate of patients with malignant tumors of the ovaries by 3% (from 32 to 35%), and in the United States - by 4% (from 35 to 39%) is due not so much to improving diagnosis, but due to implementing effective platinum-based chemotherapy in the treatment of disseminated forms of ovarian cancer and germinogenic tumors [4, 5]. To date, the "gold standard" for treatment of the IB-IIIC stages is surgical intervention with the subsequent rate of post-operative chemotherapy. At the same time the drug of choice is platinum preparations. The mechanism of action of platinum derivatives is associated with DNA damage, resulting in the formation of so-called cisplatin-DNA adducts, which, in turn, block replication, transcription and suppress the proliferation of malignantly transformed cells [4]. Resistance to platinum preparations is considered as a multifactorial phenomenon, which is due to a decrease in intracellular cytostatic accumulation, increased activity of glutathione detoxification systems and metallothioneins, disorders of the repair system of damaged DNA etc. [6-8] Depending on the progression of the disease, it is customary to distinguish between the following types of ovarian cancer: platinum-refractory (progressing during first-line chemotherapy with the inclusion of platinum preparations), platinum-resistant (progressing within 6 months after the completion of first-line chemotherapy with the inclusion of platinum preparations) and platinum-susceptible (progressing more than 6 months after the completion of first-line chemotherapy) [6]. Purpose of the study: to determine the platinum-resistance biomarkers in patients with ovarian cancer. Material and methods. The research was performed not on the basis of the regional oncology clinic (Odessa, Ukraine). 29 platinum-resistant patients with verified ovary cancer of IIIB-IIIC stages were examined, who received 6 courses of adjuvant chemotherapy with platinum preparations (cisplatin 75-100 mg/m2 intravenously with hydration and forced diuresis every 3 weeks) in the postoperative period. As control, 26 patients with non-recurrence of the disease performed for 6 months post-treatment observation (platinum-susceptible tumors) were observed. The criteria for the relapse registration, according to FIGO recommendations, were the levels of markers of CA-125, NE4 and CT data of the pelvic organs, abdominal cavity and retroperitoneum, as well as the patient's objective examination [9]. All patients analyzed the possible risk factors for resistance to platinum at the level of the body and tissues, including analysis of clinical and anamnestic characteristics, risk factors  596 for ovarian cancer, analysis of potential predictors of platinum resistance. Expression of endothelial growth factor, vascular endothelial growth factor receptors, cyclin D, cyclin E, p53, pAkt, Bcl-2, sarvivin, ABC transporter A1 in tumor tissue by immunohistochemical method [11] was studied. Additionally, local activity of nitric oxide, expression of catecholamines in erythrocytes and intracellular sulfur activity in tumor tissue [12] were analyzed. A comparative analysis of the data was carried out using Fischer's exact criterion and the besserial correlation analysis. Statistical analysis of data was carried out using the Statistica 10.0 (Dell StatSoft Inc.) program [13]. Research results It was found that in platinum-susceptible patients, VEGF expression in tumor tissue was 55 (27; 122) pg/mg, while platinum-resistant 95 (45-147) pg/ml (p> 0.05). The expression of VEGFR-1 in platinum-resistant patients was 2.4 (1.9-3.2) pg/ml, and platinum-sensitive 2.5 (2.0-3.0) pg/ml. In contrast, the expression of VEGFR-2 was 170 (120-222) pg/ml and 165 (150-190) pg/ml, respectively (p> 0.05). The content of pAkt was 0.2 (0.1- 0,3) pg/ml, and in platinum-sensitive ones - 0,5 (0,3-0,8) pg/ml. The content of Bcl-2 was 45 (25-135) pg/ml and 117 (35-225) pg/ml, respectively. The protein content of p53 in tumor tissue of platinum-sensitive patients was 4.5 ± 0.7 U/ml, while in the tissue of platinum-resistant tumors - 3.9 ± 0.6 U/ml only (p>0,05). It was also found that in platinum-resistant cases, a positive reaction to the content of survivine was determined both in the cytoplasm and within the nucleus. Instead, in platinum-susceptible patients, in most cases (92.3%) only a positive response was recorded in the cytoplasm. For platinum-resistant cases of ovarian cancer, the expression of NOS (an average of 1.2±0.2 points) and a high content of intracellular sulfur (3.8±0.2 points) were characteristic declining, whereas in platinum-sensitive cases, respectively, 3.2±0, 4 and 2.7±0.3 points (p <0.05). The content of catecholamines in erythrocytes of patients with ovarian cancer was significantly higher in platinum-resistant cases (up to 3.0 ± 0.03 granules/RBC), whereas in platinum-sensitive cases this figure was 2.6 ± 0.02 granules/RBC. Positive reaction to cyclin D content was found in 4 (13.8%) platinum-resistant patients, while platinum-susceptible ones were found in 5 (19.2%) patients. Positive response to cyclin E was determined in 6 (20.7%) in platinum-resistant patients and in 4 (15.4%)  597 platinum-susceptible patients. Statistically significant differences were not found for these indices (p> 0.05). Positive reaction to ABCA1 was detected in 9 (31.0%) platinum-resistant and 5 (19.2%) platinum-susceptible ones (p<0,05). In the course of the correlation analysis, it was found that the most pronounced relationship exists between the values of survivin expression, local activity of nitric oxide, the expression of glutathione dependent enzymes, the content of catecholamines in erythrocytes, and the expression of ABCA1 transporter (Table 1) Table 1 Correlation between the biomarkers of platinum resistance  VEGFR-1 VGFR-2 pAkt Bcl-2 p53 Surv. NOS S KCH C.D C.E ABCA1 VEGF 0,12 0,24 -0,08 -0,11 0,16 0,25 0,27 -0,18 -0,09 0,15 0,18 0,26 VEGFR-1  0,22 0,10 -0,09 0,07 0,19 0,21 0,12 0,05 0,11 0,14 0,12 VGFR-2   0,19 -0,08 -0,12 0,15 0,27 0,06 -0,11 0,09 0,12 0,24 pAkt    0,13 -0,02 0,19 0,15 0,09 -0,07 0,18 0,22 0,13 Bcl-2     0,18 0,27 0,13 -0,14 0,17 -0,08 -0,19  0,16 p53      0,23 0,06 -0,17 0,09 0,17 -0,15 0,05 Surv.       0,39 -0,33 0,35 0,28 0,29 0,54 NOS        0,42 0,39 0,30 0,28 0,59 S         0,33 -0,27 -0,28 0,53 KCH          0,31 0,33 0,45 C.D           0,62 0,41 C.E            0,43  The evidence suggests that there are common mechanisms for influencing the platinum resistance processes and the appropriateness of control of the level of expression of survivin, local activity of nitric oxide, expression of glutathione dependent enzymes, the content of catecholamines in erythrocytes, and the expression of the ABCA1 transporter in tumor tissue in patients with ovarian cancer. Conclusion: 1. The expression of ABCA1 is higher in platinum-resistant cases of ovarian cancer. 2. The most pronounced relationship exists between the values of survivin expression, local activity of nitric oxide, the expression of glutathione dependent enzymes, the content of catecholamines in erythrocytes, and the expression of ABCA1 transporter  References: 1. Epidemiology Working Group Steering Committee, Ovarian Cancer Association Consortium Members of the EWG SC, in alphabetical order:, Doherty JA, Jensen A, Kelemen LE, Pearce CL, Poole E, Schildkraut JM, Terry KL, Tworoger SS, Webb PM, Wentzensen N.  598 Current Gaps in Ovarian Cancer Epidemiology: The Need for New Population-Based Research. J Natl Cancer Inst. 2017 Oct 1; 109(10).  2. Doherty JA, Peres LC, Wang C, Way GP, Greene CS, Schildkraut JM. Challenges and Opportunities in Studying the Epidemiology of Ovarian Cancer Subtypes. Curr Epidemiol Rep. 2017 Sep;4(3):211-220 3. Ivchenko A.L. Rak yaichnikov: sovremennyye aspekty diagnostiki. Kharkívs'ka khírurgíchna shkola. 2015. 4(73): 147-151 (in Russian) 4. Francis J, Coakley N, Elit L, Mackay H; Gynecologic Cancer Disease Site Group. Systemic therapy for recurrent epithelial ovarian cancer: a clinical practice guideline. Curr Oncol. 2017 Dec;24(6):e540-e546.  5. Corrado G, Salutari V, Palluzzi E, Distefano MG, Scambia G, Ferrandina G. Optimizing treatment in recurrent epithelial ovarian cancer. Expert Rev Anticancer Ther. 2017 Dec;17(12):1147-1158.  6. Sonego M, Pellizzari I, Dall'Acqua A, Pivetta E, Lorenzon I, Benevol S, Bomben R, Spessotto P, Sorio R, Gattei V, Belletti B, Schiappacassi M, Baldassarre G. Common biological phenotypes characterize the acquisition of platinum-resistance in epithelial ovarian cancer cells. Sci Rep. 2017 Aug 2;7(1):7104. 7. Slaughter K, Holman LL, Thomas EL, Gunderson CC, Lauer JK, Ding K, McMeekin DS, Moore KM. Primary and acquired platinum-resistance among women with high grade serous ovarian cancer. Gynecol Oncol. 2016 Aug;142(2):225-30.  8. Shafrir AL, Babic A, Tamimi RM, Rosner BA, Tworoger SS, Terry KL. Reproductive and hormonal factors in relation to survival and platinum resistance among ovarian cancer cases. Br J Cancer. 2016 Nov 22;115(11):1391-1399.  9. Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C; ESMO Guidelines Working Group. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct;24 Suppl 6:vi24-32 10. Tyulyandin S.A., Moiseyenko V.M. Prakticheskaya onkologiya. M., 2004 784 s. (in Russian) 11. Immunohistochemistry (IHC) Handbook Retrieved from https://images.novusbio.com/design/BR_IHCGuide_011017_web.pdf 12. Rybin A. I., Lysenko M.A., Rysina A.I. Osoblyvosti systemy sanoheneza u khvorykh na rak yayechnykiv, shcho rezystentni do khimioterapiyi preparatamy platyny.  599 Zbirnyk naukovykh pratsʹ Asotsiatsiyi akusheriv-hinekolohiv Ukrayiny. 2014. 1-2. 251-254. (in Ukrainian) 13. Khalafyan A.A. Sovremennyye statisticheskiye metody meditsinskikh issledovaniy. Monografiya. – M.:.2014. 320 (in Russian) 

Modern strategies of platinum resistance overcoming in patients with the serous ovarian cancer

Rybin, Andriy

Akademicka Platforma Czasopism

Rybin Andriy. Modern strategies of platinum resistance overcoming in patients with the serous ovarian cancer. Journal of Education, Health and Sport. 2018;8(11):594-599. eISNN 2391-8306. DOI http://dx.doi.org/10.5281/zenodo.2535662

http://ojs.ukw.edu.pl/index.php/johs/article/view/6453

 

 

 

 

The journal has had 7 points in Ministry of Science and Higher Education parametric evaluation. Part b item 1223 (26/01/2017).

1223 Journal of Education, Health and Sport eISSN 2391-8306 7

© The Author(s) 2018;

This article is published with open access at Licensee Open Journal Systems of Kazimierz Wielki University in Bydgoszcz, Poland

Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium,

provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license

(http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited.

This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted, non commercial

use, distribution and reproduction in any medium, provided the work is properly cited.

The authors declare that there is no conflict of interests regarding the publication of this paper.

Received: 19.11.2018. Revised: 22.11.2018. Accepted: 30.11.2018.

 

 

Modern strategies of platinum resistance overcoming in patients with the serous ovarian cancer

 

Andriy Rybin

 

Odessa National Medical University, Odessa, Ukraine

Assistant Professor, Surgical Department №4 with oncology course

 

Abstract

The study was aimed to determine the platinum-resistance biomarkers in patients with ovarian cancer. The expression of ABCA1 is higher in platinum-resistant cases of ovarian cancer. The most pronounced relationship exists between the values of survivin expression, local activity of nitric oxide, the expression of glutathione dependent enzymes, the content of catecholamines in erythrocytes, and the expression of ABCA1 transporter

Key words: ovarian cancer, platitum resistance, biomarker

NEUROSURGERY ENTHUSIASTIC WOMEN SOCIETY

Odessa National Medical University Institutional Repository

http://www.ojs.ukw.edu.pl/index.php/johs/article/download/6453/8148

Modern strategies of platinum resistance overcoming in patients with the serous ovarian cancer

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