Rublоvа T. Features of combined effects of ionizing radiation and anticancer drugs on the activation of cеrаmide-mediated apoptosis of Guerin's carcinoma.

Object: cеrаmide-mediated apoptosis in Guerin carcinoma induced by the combined influence of ionizing radiation and chemotherapy. Objective: to increase the activation of cеrаmide-mediated apoptosis in Guerin carcinoma by using combined influence of ionizing radiation and chemotherapy based on determining the characteristics of the influence on the content and metabolism of bioactive sphingolipids. Methods: chromatographic, spectrophotometric (determination of lipids content), radionuclide (inclusion of 14C-labeled precursors of the endogenous lipids to investigate their metabolism and study the acid Zn2+-dependent sphingomyelinase activity), morphological, dosimetry, statistics. Results and novelty: the features of the combined influence of ionizing radiation of different energy bands (X-ray and high-energy photon) and chemotherapy (Taxotere, Сisplatin, Еtoposide) on accumulation and metabolism of proapoptotic lipid cеrаmide in the Guerin's tumor and sphingomyelin cycle activity in serum of tumor-bearing rats. It was established that the use of combined effects of IR and anticancer drugs leads to increased proapoptptic lipid cеrаmide content and synthesis of cеrаmide and sphingosine compared to separate IR action, indicating the increase of tumors sensitivity to radiation due to radiomodification. It plays an important role in the induction of cеrаmide-mediated apoptosis. The different mechanisms of activation of cеrаmide accumulation in the tumor under conditions of combined effects of fractionated radiation of different energy range (X-ray and highly effective photon radiation) and chemotherapy were identified: Тaxotere induces cеrаmide content growth primarily through activation of synthesis de novo, cisplatin stimulates the producing of cеrаmide due to enzymatic hydrolysis of sphingomyelin. Etoposide induces accumulation of CM in both ways. For the first time a synergy effects of ionizing radiation of different energy range and chemotherapeutic drugs on the cеrаmide level in the tumor were identified. For the first time it is proved that the combined effect of different energy ranges IR and Еtoposide promotes activation of sphingomyelin cycle in serum leading to accumulation of cеrаmide, and can be considered as a new mechanism of radiation-induced apoptosis of Guerin's tumor. The work demonstrates the possibility to use the level of acid Zn2+-dependent sphingomyelinase activity in the serum of patients with non-small cell lung cancer for monitoring the effectiveness of chemoradiation treatment. The degree of implementation: 15 scientific publications, newsletter. Application area: set out in the Theoretical principles recommended for inclusion in the curriculum of higher education establishments, where "Radiobiology", "Radiation Medicine", "Radiation Oncology" courses are taught.