МЕТАБОЛИЧЕСКАЯ МОДУЛЯЦИЯ ПРОТИВООПУХОЛЕВОГО ЭФФЕКТА ЦИТОСТАТИКОВ В ЭКСПЕРИМЕНТЕ И КЛИНИКЕ

In the experimental intraperitoneal chemotherapy with cyclophosphamide for sarcoma 45 and peritumoral administration of the factors inhibiting the Krebs cycle (diphenhydramine and ATP) histological, ultrastructural and immunocytometric indicators characterizing the development of the involutive processes of the tumor and its regression were studied. Modeling of metabolic microenvironment on the background of systemic neoadjuvant chemotherapy in patients with the stages T3-4N0-3M0 breast cancer led to an increase in antitumor effect. Assessment of tumor response was correlated with cytochemical indicators of the status of the key enzymes of the Krebs cycle (SDH, -GPDH) in lymphocytes of peritumoral area.При экспериментальной  внутрибрюшинной химиотерапии циклофосфаном саркомы 45 и перитуморальном введениифакторов, ингибирующих цикл Кребса (дифенгидрамин  и АТФ) изучены гистологические,  ультрастуктурные и иммуноцитометрические показатели, характеризующие  развитие  инволютивных процессов  опухоли и ее регрессии.  Моделирование метаболического микроокружения на фоне проведения системной неоадьювантной химиотерапии у больных раком молочной железы Т 3–4N0–3М0  привело к увеличению непосредственного противоопухолевого эффекта.  Оценка ответа опухоли коррелировала  с цитохимическими показателями  состояния ключевых ферментов  цикла Кребса (СДГ,  -ГФДГ) в лимфоцитах перитуморальной зоны

ВЛИЯНИЕ НУКЛЕОСПЕРМАТА НАТРИЯ НА ХАРАКТЕР ИНТЕГРАЛЬНЫХ РЕАКЦИЙ ОРГАНИЗМА ПРИ КОМБИНИРОВАННОМ ЛЕЧЕНИИ ЗЛОКАЧЕСТВЕННЫХ ОПУХОЛЕЙ ОРГАНОВ ГОЛОВЫ И ШЕИ

The development of adaptation responses to sodium nucleospermate during postoperative chemotherapy was studied in 20 patients with stage III–IV head and neck cancer. Unidirectional transition of different background reactions to acute and chronic stress with leucocytosis level of 14,0×109 /L was observed after injecting the agent. This effect was short-term and reversible. On day 6, the development of anti-stress reactions of training and activation with increase in the level of lymphocytes and upper normal limits of leukocyte count was registered, thus showing positive biological and clinical effect.Проведено изучение развития общих адаптационных реакций у 20 больных с опухолями органов головы и шеи III–IV стадий в ответ на воздействие нуклеоспермата натрия при проведении послеоперационной химиотерапии. После введения препарата наблюдался однонаправленный переход спектра различных фоновых реакций в стрессорный тип острой и хронической формы с уровнем лейкоцитоза 14,0×109 /л. Этот эффект имел краткосрочный и обратимый характер. На 6-е сут регистрировали развитие антистрессорных реакций тренировки и активации с повышением уровня лимфоцитов и содержанием лейкоцитов на верхних границах нормы, что имело позитивный биологический и клинический смысл

INFLUENCE OF SODIUM NUCLEOSPERMATE ON THE NATURE OF THE BODY’S INTEGRATED REACTIONS IN COMBINED MODALITY TREATMENT FOR HEAD AND NECK CANCER

The development of adaptation responses to sodium nucleospermate during postoperative chemotherapy was studied in 20 patients with stage III–IV head and neck cancer. Unidirectional transition of different background reactions to acute and chronic stress with leucocytosis level of 14,0×109 /L was observed after injecting the agent. This effect was short-term and reversible. On day 6, the development of anti-stress reactions of training and activation with increase in the level of lymphocytes and upper normal limits of leukocyte count was registered, thus showing positive biological and clinical effect

A60

It has previously been shown that additional local electromagnetic impact on the tumor en-hances the systemic antitumor effect of low-intensity electromagnetic radiation (EMR) used in the activation therapy regimes designed by Garkavi L.H. et al. (1990–2008). At the same time the question of the influence of weak EMR, applied to the peritumoral area, on the tumor development has not been studied. The aim of the study was to investigate the changes in the tumor caused by low-intensity microwave electromagnetic radiation of bioeffective frequency that acted on the head and peritumoral zone. Materials and methods: The effects of resonance radiation (RR) with frequency corresponding to that of one of the water-containing medium radiations – 1 GHz (“SPE-effect”) – were studied on 53 adult male outbred white rats with transplantable sarcoma 45. Special anticancer agents were not used. The power flux density of RR was less than 1 μW/cm2, surface area of the emitter – 4 cm2, 3–10 min. exposure depending on algorithms of the activation therapy. RR exposure in different groups of animals was localized to the head only, or to the peri-tumoral area only, or successively to the head and peritumoral area (“double” exposure). The course lasted for 4 weeks. The exposure effect was assessed according to the dynamics of the tumor size and results of the light and electron microscopy analysis of tumor changes (JEOL JEM-1011, Japan). Results: The effect of RR in different groups of animals depended on the exposure localization. Central systemic exposure was decisive. The group receiving RR localized to the head showed regression of the tumor or inhibition of its growth in 60% of animals – almost complete tumor regression in 10% and tumor growth inhibition by 70% in the rest cases. RR to the peritumoral area did not show significant influence on the tumor development, while it increased antitumor effect of the central exposure (p < 0.01–0.05). Antitumor effect was registered in 77% of the animals receiving the “double” RR exposure: 30% – morphologically verified complete regression, 24% – partial regression (tumor shrinkage by 2–2.5 times) and tumor growth inhibition by 40% was detected in 23% of animals. Regressing tumor, unlike sarcoma 45 with an active growth, was characterized by significant thickening of the capsule (by 7 times, p < 0.01) and increased intensity of lymphoplasmacytic infiltration (p < 0.01). Immune system cells were present in the capsule, subcapsular zone and as leukocytic barrier in peritumoral area of the conjunctive tissue of up to 170 μm width. Different numbers of lymphocytes and plasma cells were noted in tumor cells. Macrophages were found. Migrating lymphocytes were often noted in the vessels among tumor cells. Electron microscopy showed multiple contacts of lymphocytes with the surface of tumor cells through cytoplasmic excrescences. Such lymphocytes had distinct signs of activation. Simultaneous contacts of lymphocytes and macrophages among themselves and with tumor cells were found. Analysis of ultrastructural characteristics of cells in regressing tumors and detection of collagen in intercellular spaces during histochemical examination of tumor tissues showed the increase in the degree of differentiation of some sarcoma 45 cells. Conclusion: Possibility to increase the systemic antitumor effect of the low-intensity microwave radiation with an additional weak exposure on the peritumoral area was demonstrated for the first time. Damaging effect of RR on tumor was mediated by the changes in composition and activity of elements of the tumor’s immune microenvironment and by the increase in the degree of differentiation of some tumor cells, probably under the influence of bioactive factors of leukocytic origin

A66

In previous experiments the self-dependent antitumor effect of magnetite nanoparticles (NPs) injected in peritumoral area in form of magnetic fluid (MF) was shown. Elucidation of the mechanisms of this phenomenon is of theoretical and practical interest. The aim of the study was to investigate the cellular and ultrastructural changes in the tissue tumors regressed under the influence of magnetite NPs, as well as the composition of the cells of the immune system in the peritumoral area. Materials and methods: The study was carried on white male rats, 180–200 g, with transplanted sarcoma 45 (59) or Pliss lymphosarcoma (50). Special antitumor agents were not used. Magnetite NPs (10 ± 2 nm) were applied in the form of the water-based MF. Original MF (20 kA/m) was diluted with saline in different degree and was injected into peritumoral zone along the tumor borders at a distance of 1.5 cm twice a week in a volume of 0.4–0.9 ml (depending on the animal weight) within 3 weeks. Special anti-tumor agents were not used. At the end of the experiments fragments of the tumor and surrounding tissue were taken for research. The study of changes in the tumor and peritumoral area were performed by the methods of cytology, histology, histochemistry, electron microscopy (microscope JEOL JEM-1011, Japan), flow cytometry, X-ray fluorescence spectroscopy (spectrometer M4 Tornado Bruker). Results: At a dilution of the original MF in 30 times the treatment was effective in 75% of animals. Complete and partial (more than 2-fold) tumor regression was observed in 2/3 cases. In rats with Pliss lymphosarcoma tumor regression on 70–100% has been reported in 20–40% cases. The results of microscopic examination of sarcoma 45 with partial regression showed significant changes in their immune microenvironment compared with the cases of progressive tumor growth (p < 0.05–0.01). This was expressed in the increase in the number of lymphocytes and plasmacytes (respectively, in 12 and 2.5 fold), and in the appearance of macrophages and basophils that were missing in tumors with progressive growth. The results of flow cytometry of tissue from the tumor as well as from peritumoral zone indicate the predominance of plasmacytes in the case of inhibition of tumor growth and increasing the proportion of mature T lymphocytes in the cases of tumor regression (more than 1.5 times, p < 0.05). By electron microscopy, it was shown that in the cases of efficiency of the MF in addition to necrosis, observed also in growing tumors, such types of cell death were marked as apoptosis and autophagy. Numerous signs of activation of cell–cell interactions involved cells of the immune system were revealed. Different groups of 2–4 contacting cells (macrophages, lymphocytes, plasmacytes, mast cells, tumor-associated fibroblasts and neutrophils in various combinations) with signs of metabolic activity were marked. X-ray fluorescence spectroscopy preliminary results in rats with Pliss lymphosarcoma regression indicated dense arrangement of magnetite NPs and their aggregates in the peritumoral area and their practical absence in tumor. Conclusion: The study results reflect the changes in the immune microenvironment of experimental tumors under effective action of magnetite NPs and indicate significant activation of local immune processes caused by these factors