The anticancer activity of Curaxin CBL0137, a DNA-binding small molecule with chromatin remodulating effect, has been demonstrated in different cancers. Herein, a comparative evaluation of CBL0137 activity was performed in respect to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia and multiple myeloma (MM) cultured in vitro. MTT assay showed AML and MM higher sensitivity to CBL0137’s cytostatic effect comparatively to other hematological malignancy cells. Flow cytometry cell cycle analysis revealed an increase in subG1 and G2/M populations after CBL0137 cell treatment, but the prevalent type of arrest varied. Apoptosis activation by CBL0137 measured by Annexin-V/PI dual staining was more active in AML and MM cells. RT2 PCR array showed that changes caused by CBL0137 in signaling pathways involved in cancer pathogenesis were more intensive in AML and MM cells. On the murine model of AML WEHI-3, CBL0137 showed significant anticancer effects in vivo, which were evaluated by corresponding changes in spleen and liver. Thus, more pronounced anticancer effects of CBL0137 in vitro were observed in respect to AML and MM. Experiments in vivo also indicated the perspective of CBL0137 use for AML treatment. This in accordance with the frontline treatment approach in AML using epigenetic drugs.
Introduction. Natural killer T lymphocytes (NKT) take place between the innate and acquired immune response. The ability of these cells to activate the antitumor immune response and inhibit immunological activity makes them the target of research in cancer patients. The radicality of surgical treatment of patients with metastatic melanoma (stage III–IV) is relatively conventional. In this regard, the possibility of adjuvant effective therapy of melanoma is actively investigated worldwide.The aim of the study is investigation of the importance of increasing the number of NKT cells in the peripheral blood of patients with metastatic melanoma after radical surgical removal of the tumor. Patients were treated with adjuvant regimen antitumor autologous dendritic cell therapy in form of vaccination.Materials and methods. The study included 39 patients with stage III and IV metastatic melanoma with regional and / or distant metastases after radical surgery. From the peripheral blood monocytes of each patient, an autologous vaccine was created from mature dendritic cells loaded with tumor lysate. The therapy continued until objective progression. The study included patients who received from 5 to 120 injections. The follow-up period ranged from 5 to 168 months.Results. It was shown that 14 (36 %) of patients had the number of NKT cells exceeding the norm (0–10 %) and in the course of vaccine therapy they had the progression of the disease in the period up to 2 years. In patients with relapse-free course of the disease in vaccine therapy (n = 13), the number of NKT lymphocytes did not exceed the norm both before and during therapy. Significantly shorter time to progression was revealed in patients with high initial content of NKT lymphocytes compared with patients with normal indices of NKT cells (6.5 months) – 95 % confidence limit 2,4–10,7 % vs 96,2 months (95 % confidence limit 63.8–128.6 %). Conclusion. An increased number of NKT cells in patients with stage III–IV metastatic melanoma after radical surgical treatment is a marker of early progression.
Резюме. Химиотерапия является одним из основных методов лечения распространенных форм рака молочной железы. Установлено, что клиническая эффективность различных химиопрепаратов во многих случаях зависит не только от их прямого цитостатического и/или цитотоксического действия на опухолевые клетки, но и от их способности модулировать фенотип опухолевых клеток и воздействовать на противоопухолевый иммунный ответ. При этом решающее значение имеет исходное состояние иммунной системы организма и ее реакция на проводимое лечение. В ответе на опухоль участвуют клетки врожденного и адаптивного иммунитета (NK-, NKT-, Т-клетки). Эти популяции являются гетерогенными и содержат в своем составе как клетки с противоопухолевой активностью, так и регуляторные (супрессорные) клетки, подавляющие иммунный ответ и способствующие опухолевой прогрессии. Целью настоящей работы явилось определение связи исходного состояния клеточного иммунитета больных с местно-распространенным раком молочной железы с тройным негативным фенотипом и клиническим эффектом химиотерапии (цисплатин + доксорубицин/паклитаксел), а также изучение влияния проведенного лечения на субпопуляционный состав лимфоцитов периферической крови пациенток. Отмечался момент наступления прогрессирования заболевания, определялись общая выживаемость и выживаемость без прогрессирования. У 25 из 53 (47,2%) включенных в исследование пациенток в течение периода наблюдения (35,5 месяцев) заболевание прогрессировало. У 28 из 53 (52,8%) прогрессирования заболевания не наблюдалось. Иммунологическое обследование пациенток включало иммунофенотипирование лимфоцитов периферической крови и определение цитотоксической активности NK-клеток до и после химиотерапии. Определяли процентное содержание эффекторных и регуляторных популяций лимфоцитов. Полученные результаты показали, что до начала лечения отмечались различия в отклонениях процентного содержания клеток некоторых популяций лимфоцитов от контроля между группами без прогрессирования и с прогрессированием заболевания. Наиболее значительные различия касались NKT-клеток и лимфоцитов, экспрессирующих активационный маркер CD25. Снижение количества NKT-клеток и акти-Адрес для переписки: Кадагидзе Заира Григорьевна ФГБУ «Национальный медицинский исследовательский центр онкологии имени Н.Н. Блохина» Министерства здравоохранения РФ 115478, Россия, Москва, Каширское шоссе, 24. Тел.: 8 (495) 324-94-74.
Introduction. Long-term monitoring of immune system parameters in cancer patient in FSBI “N.N. Blokhin Medical Research Center of Oncology” of the Ministry of Health of Russia, as well as the absence of an immunological research algorithm and a spectrum of significant markers, served as the basis for this study.Purpose. To present reference values and determine the normal range for subpopulations of systemic immunity lymphocytes.Materials and methods. The phenotype of peripheral blood lymphocytes was studied in 186 healthy donors (86 men and 100 women), mean age 41,9 ± 12,5 years. To assess the multivariate phenotype by flow cytometry, monoclonal antibodies to CD45, CD3, CD4, CD8, CD16, CD56, CD19, CD25, CD28, CD11b, CD127, HLA-Dr, TCR-γ / δ, Perforin and Granzime B labeled various fluorochromes.Results. A panel of markers of immunocompetent cells of systemic immunity was developed as a basis for assessing the state of the immune system of cancer patients. Reference values and normal boundaries are given for characterizing the linearity of cells with detailing of the phenotypic and functional heterogeneity of the population of CD8+-lymphocytes, activation markers and the pool of naive cells; characteristics of various types of regulatory cells, functional activity of cells of the effector link of immunity. A comparative analysis of immunoregulatory indices was carried out and the vulnerability of the formula CD3+CD4+/CD3+CD8+ to the CD4+/CD8+ index was proved.Conclusion. The spectrum of the proposed indicators is the product of many years of research carried out in the laboratory of clinical immunology of the Federal State Budgetary Institution “N.N. Blokhin National Medical Research Center of Oncology” оf the Ministry of Health of the Russian Federation, in order to search for significant criteria for assessing the state of the immune system in cancer.
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