A60: The role of metabolic acidosis of peritumoral zone of tumor in enhanced efficiency of antitumor cytostatics

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• 作者：A. Shihlyarova ; E. Sheiko ; T. Kurkina ; L. Vladimirova ; N. Abramova ; G. Zhukova
• 刊名：European Journal of Cancer Supplements
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：13
• 期：1
• 页码：52-53
• 全文大小：45 K

文摘

Metabolic acidosis is a feature of many extreme physiological and pathological conditions; it is characterized by mitochondria dysfunction, increased membrane permeability and changes in the conformation of the protein molecules in violation of their enzymatic properties. In acidosis, intracellular pH shifts to the acidic side, which gives antitumor effect to the cytostatic agent the tumor was resistant to. It is known that the peritumoral zone is a buffer between the tumor and healthy tissue, so abnormalities in the tumor microenvironment changing conditions in peritumoral area will likely affect the tumor status and its response to antitumor therapy. The degree of tissue metabolic acidosis in affected area can be increased by blocking the activity of mitochondria and their contribution to the energy supply of the cells and using pharmacological agents that cause separation of processes of cellular respiration and oxidative phosphorylation. Thus, the conditions of energy blockade can be created in the perifocal area of the tumor. The aim was to study the possibility of increasing the influence of antitumor cytostatic by modeling damages of the energy forming processes in the peritumoral area of the tumor through the creation of metabolic acidosis.

Material and methods

Experimental work fragment was carried out in 60 rats with sarcoma 45 (S45) transplanted under the back skin. Cyclophosphamide (C) was administered intraperitoneally twice at a dose of 5 mg/kg. On the tumor peritumoral area perimeter (in 4 points) 0.25 ml of a 1% solution of ATP or 1% solution of diphenhydramine (D) were administered. Clinical studies were performed on 60 patients diagnosed with breast cancer. These patients underwent two cycles of CMFA chemotherapy: C 800 mg/m², methotrexate 30 mg/m², fluorouracil 2000 mg/m², doxorubicin 80 mg/m[b]; on a background of peritumoral injection of 0.5 ml of a 1% solution of ATP or 1% solution of D.

Results

Modelling of metabolic acidosis in peritumoral area was shown to result in dissociation of respiration processes and oxidative phosphorylation of cells (suppression of SDH activity by ATP by 62% and D by 57.9% and an increase in activity of αGFDG by ATP and D by 154.7%) the ratio of SDH and αGFDG less than 1. Morphologic study of S45 showed the development of wide connective border in the subcapsular zone with the inclusion of red blood cells, lymphocytes, fibroblasts, histiocytes. The signs of tumor cell death by activation of apoptosis were observed: shrinkage and reduction in cell volume, chromatin hyper condensation, fragmentation of organelles and nucleus, a large amount of coarse bundles of microfilaments, the presence of apoptotic cells. Tumor tissue was infiltrated predominantly with CD3 and CD161a cells, CD45a indicators decreased by 3–4.5 times.

The analysis of antitumor effect in breast cancer patients depending on factors of energy processes inhibition revealed that complete tumor regression only in combination with ATP occurred in 14.2%, and D-in 18.8%, partial regression using ATP was 71–5%, D – 62.5%. Tumor progression was not observed.

Conclusion

Modulating abnormalities in energy metabolism due to metabolic acidosis of tumor microenvironment on the background of systemic chemotherapy, one can achieve activation of additional pathogenetic mechanisms of inhibition of tumor growth and tumor cell death. It is necessary to emphasize the importance of the further search for factors of pathogenetic mechanisms and therapy of the influence on the tumor, including the modulation of acidosis of peritumoraly area that opens up new perspectives in solving this problem.