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 (5×10(6) 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.

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 diffe-rent combinations of cytostatics and hormonal drugs. MATERIALS AND METHODS: 72 female Wistar rats, which underwent intraperitoneal transplantation of ascitic TOT, by 5·10(6) 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.

Treatment of large osteosarcoma in children: new approach.

AIM: To improve the treatment results of patients with locally advanced osteosarcoma with large volume using neoadjuvant chemotherapy (NACT) (ifosfamide at a dose of 18 g/ml) and planning of organ-conserving surgery by evaluating the state of tumor pseudocapsule. PATIENTS AND METHODS: A study group included 46 children aged from 7 to 18 years, mean age - 12 years. In 68% of the patients tumor volume was larger or significantly larger than 200 ml (from 27 to 2400 ml), mean tumor volume was 342 ml. All patients have been examined by X-ray radiography, CT, Doppler ultrasound. Convenient chemotherapy consisted of methotrexate at a dose of 12 g/ml, cisplatin (120 mg/ml) in combination with doxorubicin (75 mg/ml). If such chemotherapy was considered ineffective with the use of an algorithm for determination of chemotherapy efficacy, 2 cycles of chemotherapy with ifosfamide at a dose of 18 g/ml per course have been applied. At the stage of planning of organ-conserving surgery, the state of tumor pseudocapsule was analyzed. In 6 months post-operative chemotherapy was carried out with the use of methotrexate, cisplatin with doxorubicin, ifosfamide at the same doses. RESULTS: Myelotoxicity of ifosfamide treatment at a dose of 18 g/ml is comparable to that of to a course of doxorubicin + cisplatin: the depth of leucopenia was significantly higher (p < 0.05), the duration of agranulocytosis is similar after such therapies. In the study group, 69.6% patients have reached grade 3-4 pathomorphosis. Organ-conserving surgery was performed in 86.9% of the patients. Local tumor recurrence was registered in 15.2% patients of the study group. 5-year relapse-free survival was achieved in 62 ± 10% (p = 0.02), the overall 5-year survival - 76.5 ± 9% (p = 0.02). CONCLUSIONS: Introduction of ifosfamide at a dose of 18 g/ml in the treatment scheme of pediatric patients with locally advanced osteosarcoma along with individualization of pre-operative chemotherapy, pre-operative analysis of NACT efficacy and the state of tumor pseudocapsule during planning stage of organ-conserving surgery significantly improves efficacy of the therapy in patients with large tumor volume.

Helicobacter pylori infection of gastric cancer cells elevates the level of expression and activation of protein kinase D2.

AIM: To test the hypothesis, whether H. pylori infection may affect the level of PKD2 expression and/or activation in gastric cancer cells. METHODS: Studies were performed on AGS human gastric adenocarcinoma cell line, gastric tissues samples from 36 cases of different histological variants of gastric cancer. Immunohistochemical, cell and molecular biology, bacteriological and biochemical approaches have been used in this study. RESULTS: H. pylori 16S rRNA gene was detected in 97% cases of gastric tumors, and in 83% of cases csmall a, CyrillicgA gene was detected. In all tested adenocarcinoma samples cagA+ H. pylori was revealed. These cases were characterized by high level of PKD1/2 expression and autophosphorylation. In adenogenic cancer samples the presence of cagA- H. pylori was identified. Carcinoid and nondifferentiated gastric cancers contain H. pylori, with very low numbers of cagA+ copies. All cases of gastric tumors with cagA- H. pylori had very low levels of PKD1/2 autophosphorylation. AGS cell line infection with cagA- and cagA+ H. small er, Cyrillicylori resulted in elevation of PKD2 expression levels in 3.29 and 3.66 times respectively (p < 0.001). In cells infected by cag+ H. small er, Cyrillicylori the level of PKD2 transphosphorylation was 1.39 higher than in cells infected by cagA- H. pylori. For PKD2 autophosphorylation this difference was even higher - 3.27 times (p < 0.001). CONCLUSION: H. pylori infection enhanced the level of protein kinase D2 expression, trans- and autophosphorylation. The level of PKD2 autophosphorylation/activation was higher in AGS cell line inoculated of with cag+ H. pylori than in AGS cells with cagA- H. pylori. These suggest that H. pylori induces activation of PKD1/2 and could exploit PKD2 mediated signaling pathways that may contribute to the pathogenesis of gastric cancer.