Experimental Oncology, 2014, № 2

Single dose regorafenib-induced hypertensive crisis

2019-01-20T23:23:15Z

Single dose regorafenib-induced hypertensive crisis Yilmaz, B.; Kemal, Y.; Teker, F.; Kut, E.; Demirag, G.; Yucel, I. Gastrointestinal stromal tumors (GISTs) are uncommon tumors of the gastrointestinal (GI) tract. Regorafenib is a new multikinase inhibitor and is approved for the treatment of GISTs in patients who develop resistance to imatinib and sunitinib. The most common drug-related adverse events with regorafenib are hypertension, hand-foot skin reactions, and diarrhea. Grade IV hypertensive side effect has never been reported after a single dose. In this report, we present a case of Grade IV hypertensive side effect (hypertensive crisis and seizure) after a single dose of regorafenib. A 54-year-old male normotensive GIST patient was admitted to the emergency department with seizure and encephalopathy after the first dosage of regorafenib. His blood pressure was 240/140 mmHg upon admission. After intensive treatment with nitrate and nitroprusside, his blood pressure returned to normal levels in five days. Regorafenib was discontinued, and he did not experience hypertension again. This paper reports the first case of Grade IV hypertension after the first dosage of regorafenib. We can suggest that hypertension is an idiosyncratic side effect unrelated to the dosage. Key Words: hypertension, regorafenib, gastrointestinal stromal tumor.

Determination of the optimal chemotherapy drugs pretreatment time through cultivation of hemopoietic cells in CML-patients treated with tyrosine kinase inhibitors

2019-01-20T23:24:22Z

Determination of the optimal chemotherapy drugs pretreatment time through cultivation of hemopoietic cells in CML-patients treated with tyrosine kinase inhibitors Zhaleiko, I.O.; Perekhrestenko, T.P.; Bilko, D.I.; Dyagil, I.S.; Bilko, N.M. Background: Targeted therapy drugs, including imatinib, are used for inhibiting the marker oncoprotein of chronic myeloid leukemia — BCR-ABL tyrosine kinase. However, in some patients the drug resistance can emerge too rapidly and a previous treatment with chemotherapy drugs can lead to formation of resistance. Aim: To evaluate the influence of drugs that were used prior to the imatinib on the performance of the functional activity of bone marrow cells from chronic myeloid leukemia patients and their individual responses to therapy. Methods: Bone marrow aspirate from 57 patients, who were getting busulfan (19 patients) or hydroxycarbamide (38 patients) prior to imatinib was studied with cytogenetic and tissue culture methods in vitro. Results: Obtained data suggested that pretreatment with busulfan, regardless of duration, negatively affects the response to further therapy with imatinib. Instead, after using hydroxycarbamide as a previous therapy for six month, there was optimal response to imatinib. In those cases when duration of pretreatment with hydroxycarbamide was increased to a year or more, there was a suboptimal response and a resistance to imatinib therapy. In addition, there was a positive correlation between the number of cell aggregates (colonies and clusters) in semisolid agar and the duration of a prior treatment with hydroxycarbamide, if previous therapy did not exceed 20 months. With an increase of pretreatment terms to 21 months or more, such a correlation was not observed. Conclusions: These results suggest that chemotherapeutic agents (busulfan and hydroxycarbamide) may additionally contribute to the accumulation of mutations in the genome of leukemic cell clone affecting the behavior of these cells in vitro. Key Words: chronic myeloid leukemia, imatinib, pretreatment, hydroxycarbamide, busulfan, cell culture in vitro.

Impact of stromal cell components of tumor microenvironment on epithelial-mesenchymal transition in breast cancer cells

2019-01-20T23:23:14Z

Impact of stromal cell components of tumor microenvironment on epithelial-mesenchymal transition in breast cancer cells Bezdenezhnykh, N.; Semesiuk, N.; Lykhova, O.; Zhylchuk, V.; Kudryavets, Y. Background: Cell and tissue homeostasis results from the dynamic balance of cell – cell and cell – extracellular component crosstalk that regulates proliferation, differentiation, and apoptosis of cells as well as secretion and activation of soluble factors and/or deposition of extracellular matrix (ECM) components. Aim: The aim of the work was to study the crosstalk between tumor cells and stromal cell components using noncontact co-cultivation in vitro system. Materials and Methods: Human and rat breast cancer (BC) cell lines, normal human fibroblasts (NHF) and endothelial cells, and aspirates of bone marrow (BM) of BC patients with different clinical course of the disease (groups “Remission” (BM-R) and “Progression” (BM-P)) were used in noncontact co-cultivation system in vitro. The cell growth, expression of epithelial-mesenchymal transition (EMT) and tumor stem cell markers (E-cadherin, vimentin, CD44), Ki-67, p21 and Slug were investigated using immunocytochemical analysis. Results: Analysis of expression of E- and N-cadherin, vimentin and Slug in BC cells has shown that T-47D and MRS-T5 cells possess mesenchymal phenotype, while MCF-7 and MRS cells possess mostly epithelial phenotype with a part of cells with mesenchymal patterns. Upon noncontact co-cultivation of fibroblasts with Т-47D or MRS-Т5 cells, BC cells acquired higher proliferative activity compared to the control cells (р < 0.05) or MCF-7 and MRS cells co-cultivated with fibroblasts. Upon noncontact co-cultivation of Т-47D cells with normal fibroblasts and BM cells from BC patients from group “Progression” there were observed increased quantity of CD44+ Т-47D cells (by 26%), decreased quantity of Е-cadherin+ Т-47D cells, and appearance of vimentin-positive cells. In co-cultivation variant Т-47D + NHF + BM-R (“Remission“) the quantity of CD44+ Т-47D cells significantly decreased (р < 0.005) and E-cadherin expression remained unaltered compared to control cells. At the same time, in NHF cell population (co-cultivation variant Т-47D + NHF + BM-P) there was detected significant increase of quantity of р21+-cells (р < 0.005), cytoplasmic localization of p21, and nuclear localization of Slug. Expression of vimentin did not alter in any variant of co-cultivation. Conclusion: The new integration cell system for investigation of the mechanisms of interaction between tumor cells and the tumor microenvironment in vitro was developed. The significant changes in proliferative activity of TC dependently on its ЕМT-status were detected after their interaction with fibroblasts and endothelial cells in noncontact co-cultivation system. BM cells of BC patients had different modifying influence on TC dependent on clinical BC course. The activation of ЕМT program was revealed in TC upon noncontact co-cultivation with BM cells of BC patients with progression of the disease. Key Words: breast cancer, epithelial-mesenchymal transition, microenvironment, bone marrow, co-cultivation.

Clinical significance of hormonal receptor status of malignant ovarian tumors

2019-01-20T23:23:11Z

Clinical significance of hormonal receptor status of malignant ovarian tumors Tkalia, I.G.; Vorobyova, L.I.; Svintsitsky, V.S.; Nespryadko, S.V.; Goncharuk, I.V.; Lukyanova, N.Y.; Chekhun, V.F. 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.