The antitumor efficacy of cisplatin in combination with triptorelin and exemestane therapy for an ovarian cancer ascites model in Wistar rats

Aim: To study antitumor activity of triptorelin — agonist of gonadotropin-releasing hormone and exemestane — inhibitor of aromatase in combination with cisplatin on the model of receptor-positive for estrogens and progesterone malignant transplantable ascites ova­rian tumor (OT); to assess tumor response to treatment and VEGF expression in tumor cells under different combinations of cytostatic and hormonal drugs. Materials and Methods: 36 female Wistar rats, which underwent intraperitoneal transplantation of ascites OT (5×106 cells per animal), have been involved in the study. Rats were distributed into 4 groups (9 rats in each group): group 1 — animals, which received combination of cisplatin and triptorelin; group 2 — rats treated with combination of cisplatin and exemestane; group 3 — animals, which were administered with combination of cisplatin, triptorelin and exemestane; group 4 — rats, which received combination of triptorelin and exemestane. Histological study with assessment of treatment pathomorphosis in OT and immunohistochemical study have been carried out to analyze VEGF expression in OT cells. Survival of animals has been evaluated. Results: Combination of cytostatic agent with triptorelin or exemestane has demonstrated significantly higher rates of treatment pathomorphosis (10.1 ± 0.1% and 16.2 ± 0.3%, respectively) and antiangiogenic activity in OT (21.4 ± 1.4% and 15.0 ± 1.3%, respectively), as well as the highest survival of animals (100.0 and 85.7%, respectively) as compared with the same in rats treated in regimen of monotherapy with cisplatin, triptorelin, exemestane or by combination of hormonal drugs. Among animals treated by combination of cytostatic drug with triptorelin, two were cured (22.2%), and among rats, which received cisplatin and exemestane, one animal (11.1%) was cured. Conclusions: Triptorelin and exemestane increase antitumor activity of cisplatin in respect to the transplantable malignant ascites OT and significantly increase survival of animals, especially when triptorelin and cisplatin are used in combination. Key Words: transplantable ascites ovarian tumor, rat, cisplatin, agonist of gonadotropin-releasing hormone triptorelin, inhibitor of aromatase exemestane, treatment pathomorphosis, VEGF, survival

Expression of the estrogen and progesterone receptors as prognostic factor in serous ovarian cancers

Aim: To study the expression of estrogen receptors (ER) and progesterone receptors (PR) and proliferation marker Ki-67 in ovarian tumors using immunohistochemistry, and evaluate possible prognostic significance ofthese markers. Methods: Immunohistochemical evaluation of Ki-67, ER and PR expression was performed on serous ovarian cancer (OC) tissue samples from 81 OC patients. Results: Serous OC is characterised by high proliferative activity and increased expression of steroid hormone receptors compared to nontransfomed ovarian surface epithelium. It has been shown that ER and PR expression levels depend on tumor histologic grade and the stage of the disease, and are variable between tumors of the same grade. The ER and PR expression levels correlate with OC patients’ survival. Conclusion: Proliferative activity and steroid hormone receptor status along with clinical and morphological characteristics of serous OC possess prognostic significance and may be used for evaluation of the disease cours

Clinical significance of hormonal receptor status of malignant ovarian tumors

Objectives: To study hormonal receptor status (HRS) of malignant ovarian tumors (MOT) and determine its clinical significance. Patients and Methods: Retrospective analysis of case histories of 284 patients with MOT of different genesis of I–IV stages was carried out; immunohistochemical study of paraffin-embedded tissues. The HRS for serous, mucinous ovarian cancer (OC) and sex cord-stromal tumors (SCST) was studied. The phenotype of tumors by HRS in patients with serous OC was determined; overall and relapse-free survival in these patients was evaluated depending on the tumor HRS. Results: Positive expression of ER has been registered in 66.4% of patients with serous OC, PR — in 63.4%, TR — in 53.0%; in patients with mucinous OC — 88.0; 84.0; 60.0%, respectively. Positive staining of cells of stroma-cellular tumors has been observed in 74.1% of patients for ER and 77.8% — for PR and TR. The highest number of patients with tumor phenotype ER+PR+TR+ has been observed in postmenopause — 52.4%, especially in late postmenopausal period — 39.0%. The lowest percentage of patients with mentioned phenotype has been marked in reproductive age — 20.7%. Most patients of reproductive period had phenotype of tumor ER-PR-TR- (35.1%), in late postmenopause this phenotype has been observed only in 16.2%. The patients with serous OC with the positive tumor HRS demonstrated the low indices of overall and relapse-free survival compared to the patients with receptor-negative tumors con­cerning all steroid hormones (р < 0.05). Conclusions: Positive HRS was registered in serous, mucinous OC and in SCST, high percen­tage of tumors with expression of all receptors of steroid hormones was observed at that. The highest frequency of tumors with positive HRS was recorded in patients with serous OC of late postmenopausal period. The patients with serous OC with receptor-positive tumor phenotype showed the rates of overall and relapse-free survival significantly lower compared to the patients with receptor-negative phenotype of OC. Positive HRS, the same as strong expression of TR in patients with serous OC, is a predictive factor of unfavorable course of tumor process. HRS of MOT can be regarded as the additional criterion for solution of a question concerning application of hormonal therapy as a component of complex treatment for the patients. Key Words: malignant ovarian tumors, serous ovarian cancer, hormonal receptor status, estrogen, progesterone, testosterone receptors, phenotype of tumor

Increase of antitumor activity of cisplatin using agonist of gonadotropin-realising hormone and inhibitor of aromatase on the model of ascites ovarian tumor

Aim : To study antitumor activity of triptorelin — agonist of gonadotropin-releasing hormone and exemestane — inhibitor of aromatase in monotherapy and in combination with cisplatin on the model of receptor-positive for estrogens and progesterone malignant ascites transplantable ovarian tumor (TOT), to assess therapeutic pathomorphosis and level of VEGF expression in tumor cells using diffe­rent combinations of cytostatics and hormonal drugs. Materials and methods. 72 female Wistar rats, which underwent intraperitoneal transplantation of ascitic TOT, by 5·106 cells per animal, have been involved in the study. Rats were divided into 8 groups, 9 rats in each group. Histological study with assessment of therapeutic pathomorphosis in TOT and immunohistochemical study has been carried out. Survival of animals in the studied groups has been evaluated. Results. Among animals treated in regimen of monotherapy, the most pronounced antiangiogenic activity in TOT has been observed on application of hormonal drugs (triptorelin — 39.4 ± 1.9 and exemestane — 33.9 ± 1.4%; р = 0.003), the highest grade of treatment pathomorphosis in TOT has been observed at treatment with cisplatin (11.7%; р = 0.001). Combination of triptorelin and exemestane has amplified antiangiogenic activity in TOT (12.2 ± 0.9%; р = 0.001), but has not significantly changed rates of pathomorphosis (22.1 ± 0.4%; р=0.005) and survival of animals (32.2%; р = 0.007) as compared with the same rates in rats treated with hormonal drugs in monotherapy. Significant correlation between VEGF expression and pathomorphosis has been established (relative part of viable tumor tissue (RPVTT)) in TOT (r = 0.712; р = 0.001), as well as between RPVTT and life-span of animals (r = −0.320; р = 0.007). However, lack of correlation between VEGF expression in cells of TOT and survival of rats has been determined (r = −0.194; р = 0.11). Combination of cytostatic agent with triptorelin or exemestane has demonstrated significantly high rates of therapeutic pathomorphosis (10.1 ± 0.1% and 16.2 ± 0.3%, respectively) and antiangiogenic activity in TOT (21.4 ± 1.4% and 15.0 ± 1.3%, respectively) as well as the highest survival of animals (100.0%, increase of life-span (ILS) = 231.9% and 85.7%, ILS = 205.8%, respectively) as compared with the same one in rats treated in regimen of monotherapy with cisplatin, triptorelin, exemestane or by combination of hormonal drugs. Among animals treated by combination of cytostatic drug with triptorelin, two were cured, and among rats, which received cisplatin and exemestane, one animal was cured. Conclusions. Triptorelin and exemestane increase antitumor activity of cisplatin in respect to the malignant ascitic TOT and significantly increase survival of animals, especially when triptorelin and cisplatin are used in combination. Key Words: ascites transplantable ovarian tumor, rat, cytostatic, agonist of gonadotropin-releasing hormone triptorelin, inhibitor of aromatase exemestane, pathomorphosis, VEGF, survival