Pushkar S. Pathogenetic ground for usage of directional apoptosis induction and accompanying therapy for the increase of effectiveness of radiation therapy of cancer patients.

Українська версія

Thesis for the degree of Doctor of Science (DSc)

State registration number

0508U000516

Applicant for

Specialization

  • 14.03.04 - Патологічна фізіологія

09-10-2008

Specialized Academic Board

Д 64.600.03

Essay

Object of study: effectiveness increase of radiation treatment of cancer patients.The aim of study: pathogenetic ground for usage of di-rectional induction of ceramide pathway of apoptosis, and also introducing combined antiblastoma treatment into the course of treatment with modifying accompanying therapy on the basis of detection of the pattern of malfunction of homeostasis in the course of radiation therapy with inductor of apoptosis by taxoter.Methods of study: pathophysiological, clinical laboratory and instrumental, biochemical, coagulologic, immunological, radioisotope, histological, electro-microscopic, statistical.Theoretical and practical importance of results ob-tained: new obtained data about mechanism of effect of radio modifiers of taxoter and etoposide on activation of ceramide pathway of apoptosis allowed to give pathogenetic ground and to develop method of neoadjuvant radiation therapy with tol-erant dosage of taxoter while combined treatment of patients with primary inoperable breastcancer. A patent for method of radiation therapy with induction of apoptosis by taxoter is ob-tained; method of accompanying therapy with usage of drugs of natural (animal and vegetable) origin was pathogenetically grounded and introduced into practice of clinical medicine fro prevention and correction of homeostasis malfunction while radiation therapy with taxoter. The methods of radiation treatment with directional induction of apoptosis of tumor cells with tolerant dosage of taxoter and accompanying ther-apy developed. Hypocholesterinemia, hypertriglyceridemia, increase of level of high-density lipoproteins and phenomena of hypercoagulation can be regarded as unfavorable prognostic features of oncological process.Scientific novelty: A complex experimental study was conducted of mechanisms of induction of ceramide pathway of apoptosis, mechanisms of synthesis and accumulation of proapoptosis ceramide lipid in the tumor, influence of quanti-tative contents of ceramide on intensity of apoptosis and influ-enceof medicamentous radio modifiers of taxoter and eto-poside on selective management of radio-sensitivity of tumor cells. It is experimentally established that cytostatics of taxoters and etoposides in conditions in vivo favor more than three and five times (accordingly) increase of content of proapoptosis lipid of ceramide in radio-resistant cells of Guerin's tumor, which allows the usage of these drugs as radio modifiers. Its is established that the mechanism of overcoming of radio-resistance of tumor cells of Guerin's carcinoma when using of taxoter and etoposide as radio modifiers together with local Roentgen irradiation of tumor is connected to a consider-able (4 and almost 6 times accordingly) increase of synthesis and accumulation of ceramide in them. For the first time by means of determination of activeness of synthesis of separate fractions of sphingolipids with the help of radioactive precur-sor 14C- palmitic acid different mechanisms of accumulating of ceramide in tumor cells have been shown when influenced with taxoter and etoposide. The increase of content of cera-mide and induction of apoptosis when introducing the taxoter is performed by means of synthesis of ceramide de novo; when introducing the etoposide the accumulation of ceramide is performed not only by means of its synthesis de novo but also due to transformation of sphingomyelin into ceramide and decrease of level of degradation of ceramide which is shown by low content of sphyngosin. For the first time it is experimentally proven that excessive increase of level of synthesis and accumulation of proapoptosis sphingolipid of ceramide in tumor cells when introducing etoposide is accompanied by insignificant activation (by 25%) of synthesis of pro- proliferative lipid – glucosideceramide as complex reaction to increased apoptosis death of cells. High rate of ratio ceramide/ glucosideceramide in tumor cells in comparison with control indicate domination of apoptosis orientation of etoposide effect. For the first time activation of ceramide process of apoptosis has been shown under the influence of radio modification with taxoter in the cells of tumor of patients with breast cancer. For the first time method of neoadjuvant radiation therapy is created and implemented in clinic practice with tolerant dosage of taxoter for primary inoperable breast cancer, providing high degree of reduction of tumor, possibility of tumor transformation into operable condition and also which allows to decrease the level of cataplasis of possibly remained tumor cells. For the first time patterns of changes of some systems of homeostasis (pro- and antioxidant, homeopathic, lipid metabolism, intensity of endotoxemia) of patients with breast cancer while radioactive therapy with radio modifier taxoter have been determined which allowed to develop pathogenetically grounded accompanying therapy for prevention and correction of these disorders. Degree of introduction: into educational process of de-partments of pathological physiology and oncology of Kharkiv National MedicalUniversity, Ukrainian Medical Stomatology Academy, departments of pathological physiology of Donetsk, Lugansk and Dnepropetrovsk Medical Universities, depart-ment of oncological gynecology of Kharkiv Medical Academy of advanced studies and department of radioactive medicine of Ukrainian Medical Stomatological Academy. Recommenda-tions are introduced in to practice of departments of radiation therapy of Kharkiv district clinical oncological dispensary and “Institute of medical radiology named after S.P.Grigoriev, Academician of Ministry of Science of Ukraine”. Field (area) of usage: medicine, pathophysiology, on-cology.

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