Мета: вивчення впливу комбінованої дії Х випромінення та інгібітора циклооксигенази 2 (ЦОГ 2) на рівень фактора росту ендотелію судин (VEGF) і простагландину E 2 (PGE 2) 2 в сироватці крові щурів з перевитою пух линою Герена при опроміненні в різних дозах. Матеріали і методи. 20 щурам самицям популяції Вістар масою 160-180 г з перещепленою карциномою Гере на проводили фракціоноване опромінення (5 Гр + 5 Гр) та (0,5 Гр + 0,5 Гр) зони росту пухлини на апараті РУМ 17 з інтервалом між сеансами 24 год. Препарат «Мелоксивет»-селективний інгібітор ЦОГ 2 вводили за добу до опромінення та за 2 години перед другим опроміненням (0,2 мг на 1кг маси тіла). Забір крові проводили мето дом прижиттєвої декапітації через 24 год після останньої фракції опромінення. Вміст VEGF та PGE 2 в сироватці крові визначали методом імуноферментного аналізу з використанням стандартних наборів. Результати. Після фракціонованого опромінення у сумарній дозі 1 Гр (0,5 Гр + 0,5 Гр) рівень VEGF підвищував ся у 1,5 раза порівняно з інтактним контролем, а у тварин, опромінених у сумарній дозі 10 Гр (5 Гр + 5 Гр), рівень VEGF вірогідно знижувався у 1,92 раза. Тобто, спостерігали різницю вмісту VEGF в сироватці крові щурів пухли ноносіїв залежно від доз опромінення: після опромінення сумарній дозі 1 Гр-стимуляція ангіогенезу, 10 Грзначне уповільнення цього процесу. У разі поєднаної дії опромінення (10 Гр) та інгібітора ЦОГ 2-мелоксиве ту відмічали вірогідне зниження рівня VEGF у 3,49 раза порівняно з контролем та у 1,8 раза з ізольованим оп роміненням. При цьому рівень PGE 2 також знижувався відносно ізольованого опромінення у 1,5 раза, що вка зує на інгібування ЦОГ 2. При поєднаній дії опромінення в низьких дозах (1 Гр) та інгібітора ЦОГ 2-мелокси вету спостерігали зниження рівня VEGF у 1,1 раза порівняно з контролем та у 1,7 раза відносно ізольованого оп ромінення. При цьому рівень PGE 2 також знижувався порівняно з ізольованим опроміненням у 1,1 раза. Отри мані результати свідчать про вплив поєднаної дії опромінення і мелоксивету на рівень VEGF та PGE 2, що зумов лює антиангіогенний ефект. Висновки. Доведено, що низькі дози іонізуючої радіації (1 Гр) та високі дози (10 Гр) по різному впливають на експресію VEGF, і тим самим на процеси ангіогенезу. Поєднана дія іонізуючої радіації та інгібітора ЦОГ 2 (ме локсивету) впливає на зниження рівня PGE 2, VEGF, тобто, на уповільнення ангіогенезу. У разі великих доз оп ромінення цей вплив виражений ще більше. Ключові слова: Х випромінення, інгібітор ЦОГ 2-мелоксивет, фактор росту ендотелію судин (VEGF), циклоок сигеназа 2 (ЦОГ 2), простагландин Е 2 (PGE 2), ангіогенез.

Background. COX-2 inhibitors facilitate disruption of the production of angiogenic factors, the use of which in combination with RT leads to a significant delay in tumor growth in experimental models of cancer. Purpose. Evaluation of the effectiveness of RT in combination with COX-2 inhibitor in patients with NSCLC (non-small-cell lung carcinoma). Materials and methods. The study involved 38 patients with NSCLC divided into 2 subgroups: Subgroup 1 was represented by 20 patients who received a RT course and celecoxib 100 mg/d, Subgroup 2 enrolled 18 patients who received only RT. The subgroups were comparable by sex, age, tumor location, general condition. Squamous cell carcinoma was detected in 19 (95.0%) patients of Subgroup 1 and in 9 (50%) patients of Subgroup 2. Stages I – II were diagnosed 4.4 times more frequently in Subgroup 2, stage III was 1.9 times more frequently detected in Subgroup 1 (p < 0.05). VEGF, COX-2 content was assessed before/after the RT course by means of a sandwich immunoassay (ELISA). Results. A positive effect (partial regression, stabilization) was observed equally in the subgroups: 80.0% and 77.8%. In Subgroup 1, partial regression was 5 times more frequent, the overall annual and recurrence-free survival increased by 15 and 29%, respectively. In patients of Subgroup 1, COX-2 was 2.4-fold decreased, in patients of Subgroup 2, COX-2 almost did not change. COX-2 blocking was accompanied by decreased VEGF: 1.9-fold in Subgroup 1, 1.4-fold in Subgroup 2. Changes in COX-2 and VEGF levels were consistent with the objective response after RT with celecoxib: in case of a positive effect, COX-2 level was significantly decreasing (2.3-1.9-fold), VEGF level was significantly decreasing (2.3–1.7-fold); progressive tumor growth was combined with a minor decrease in COX-2 and VEGF (1.5–1.4-fold). Conclusions. Radiation therapy in combination with COX-2 inhibitor enhances the effectiveness of treatment by increasing partial regressions and relapse-free survival. An objective response correlates with COX-2 and VEGF levels, which makes it possible to use them to assess RT effectiveness and decide on further treatment strategy.

Background. Overcoming radioresistance is an important problem in radiation oncology. Therefore, the development of new approaches to modeling the radiosensitivity of tumors in cancer patients becomes relevant and important. Cyclooxygenase-2 (COX-2) inhibitors are new agents for radiomodification in various radiation therapy schemes, the use of which slows down angiogenesis by suppressing the activity of the COX-2 enzyme. Purpose. To determine the content of indicators of radioresistance: vascular endothelial growth factor (VEGF), COX-2, prostaglandin E-2 (PGE-2) in the blood serum of patients with non-small cell lung cancer (NSCLC) and changes in their levels with different schemes of radiation therapy (RT). Materials and methods. 36 patients with NSCLC were examined and treated, who were divided into four groups: RT (the first group – 16 patients), RT with the COX-2 inhibitor – ranselex (the second group – 9 patients), RT with ranselex and cisplatin (the third group – 5 patients ) and RT with cisplatin (fourth group – 6 patients). The patients received a course of radiation treatment using a Clinac 600C linear accelerator. The classical fractionation mode was used, the total focal doses were 60–66 Gy. Cisplatin was prescribed at 30 mg/m2 per week up to a total dose (SD) of 200 mg, the COX-2 inhibitor Rancelex® at a dose of 100 mg per day (active substance – celecoxib). The levels of VEGF, COX-2, and PGE-2 in the blood serum of patients with NSCLC were determined by enzyme-linked immunosorbent assay (ELISA) before and after treatment. Results. The level of the angiogenesis marker VEGF after treatment in the group with RT decreases by 1.46 times, in the group with the combined action of RT and ranselex – 2.4 times, in the group with the combined action of PT, ranselex and cisplatin – by 3.7 times, and in the group with the combined effect of RT and cisplatin, it decreases by 1.1 times. The greatest decrease in the level of VEGF is observed with RT in combination with ranselex and cisplatin, which indicates a more effective enhancement of the antiangiogenic effect. Conclusions. It has been proven that with various schemes of RT using the COX-2 inhibitor – ranselex and cisplatin in patients with NSCLC, there is a decrease in the radioresistance markers PGE-2 and COX-2, the angiogenesis marker – VEGF, which indicates that the effect of radiomodification on the angiogenesis process is most pronounced in the combined actions of RT and both radio modifiers. The use of COX-2 inhibitors as radiosensitizers in combination with RT provides a new opportunity to increase tumor radiosensitivity.

Objective: to evaluate the levels of VEGF, COX-2, PGE-2 in comparison with the effectiveness of radiation therapy with or without a COX-2 inhibitor. Materials and methods. The study involved 38 patients with non-small cell lung cancer (NSCLC) aged 32 to 80 years (median — 66 years), stage III of the process (50 %) prevailed, histological studies revealed squamous cell cancer in 74 %. To evaluate the results of the study, patients were divided into 2 subgroups: 1 — a subgroup (20 patients who received radiation therapy (RT) in combination with a COX-2 inhibitor — ranselex), 2 — a subgroup (18 patients who received RT). Radiation therapy was performed on linear accelerators Clinac 600C. During RT, patients received a COX-2 inhibitor — ranselex 100 mg per day. To determine the content of angiogenesis factors VEGF, COX-2, and PGE-2, blood sampling was performed in patients before irradiation and after a course of radiotherapy. The content of VEGF, COX-2, and PGE-2 was determined in blood serum by ELISA using standard reagent kits: of Vector-Best CJSC (Russia) for VEGF, commercial reagent kits of Invitrogen COX-2 ELISA Kit (Great Britain) and Prostaglandin T2 ELISA Kit (Germany). Results. An elevated level of VEGF, COX-2, PGE-2 in the blood serum of patients with NSCLC before radiation treatment was revealed, which indicates the activity of neoangiogenesis processes in the tumor. It was found that in patients with NSCLC after RT in combination with the COX-2 inhibitor ranselex, a 1.9-fold decrease in VEGF was observed against a 2.4-fold decrease in the COX-2 content and 1.7-fold PGE-2. In RT without ranselex, VEGF decreased by 1.4 times and the levels of COX-2 and PGE-2 did not change, which indicates inhibition of the COX-2 inhibitor of angiogenesis. The relationship between the concentration of the pro-angiogenic factor VEGF and the levels of COX-2, PGE-2 and the objective response with which the direct effect of RT was evaluated was established. With regression of the tumor process, a decrease in the level of VEGF was observed, more pronounced in RT with ranselex, which indicates the effectiveness of RT. With progression, a consistently high level of VEGF was observed, which is an unfavorable sign and is possibly associated with the tumor resistance to the therapy and the further unfavorable course of the disease. Conclusions. The relationship between the concentration of pro-angiogenic factors — VEGF, COX-2, PGE-2 and the objective response was determined, for which the direct effect of radiation therapy with or without a COX-2 inhibitor of ranselex (regression, stabilization, progression) was evaluated. It was shown that a more pronounced decrease in VEGF content is observed after radiation therapy (RT) with ranselex compared with RT without ranselex, which indicates inhibition of COX-2 inhibitor angiogenesis, and thereby leads to an increase in the effectiveness of RT.