ANTITUMOR EFFECT OF HYDROGEL CISPLATIN ON ZEJDEL ASCITES HEPATOMA

Aims and objectives. During regional intraperitoneal chemotherapy cytostatics in prolonged dosage form, in particular, on the basis of various biodegradable hydrogels, such as dextran phosphate are applied. Aim of the study - a comparative evaluation of the antitumor activity ofcisplatin and cisplatin in prolonged dextran phosphate hydrogel form on Zajdel ascites hepatoma. Materials and methods. On 49 white no inbreed rats (n = 7) with implanted intraperitoneal Zajdel ascites hepatoma the antitumor activity of cisplatin in prolonged dextran phosphate hydrogel form with single intraperitoneal injection of the dosage from 3 to 8 mg/kg (≈ maximum tolerated dose, MTD) was evaluated in comparison with officinal cisplatin. The treatment efficacy was assessed by a statistically significant standard criteria: the absence of ascites by 32nd day of the experiment (complete remission) and an increase in life span of rats with ascites (T/C >_125 %, «treatment/control») in comparison with the rats without treatment (tumor growth control, where T/C = 100 %) or treated with officinal cisplatin. Macroscopic, pathomorphological and statistical analysis of the results were used. Results. It has been shown that hydrogel form of cisplatin compared to cisplatin was significantly more effective: complete remission 4/7-6/7 vs 0/7, T/C = 140-188 % vs 91-101 %, the volume of ascites 13,6 ± 6,6 ml vs 50,0 ± 7,9 ml (p = 0,004) because of a better tolerance. Regression analysis confirms that hydrogel form of cisplatin in used dose range significantly improves the rats survival with Zajdel ascites hepatoma, reducing the risk of death from tumor in 7-35 times and the relative risk with the dose of 5,5 mg/kg in 36 times (95 % CI3,86 + 327,60) (p = 0,002-0,005). Conclusions. The data obtained allow considering the hydrogel form of cisplatin as a promising prolonged this drug form of cisplatin by the intraperitoneal therapy and recommending it to preclinical study.

пролонгированная форма цисплатина, гидрогель фосфата декстрана, противоопухолевая активность, сравнительное изучение, асцитная гепатома Зайделя, prolonged form of cisplatin, dextran phosphate hydrogel, antitumor activity, comparable investigation, Zajdel ascites hepatoma

1. Soma D., Kitayama J., Konno T. et al. Intraperitoneal administration of paclitaxel solubilized with poly (2-methacryloxyethyl phosphorylcholine-co n-butyl methacrylate) for peritoneal dissemination of gastric cancer. Cancer Sci 2009;100(10):1979-85. DOI: 10.1111/j.1349-7006.2009.01265.x. PMID: 19604244.

2. Wang Y., Gong Ch., Yang L. et al. 5-FU-hydrogel inhibits colorectal peritoneal carcinomatosis and tumor growth in mice [Электронный ресурс]. BMC Cancer 2010;10:402. Режим доступа: http://www.biomedcentral.com/1471-2407/10/402. Дата доступа: 16.08.2010. DOI: 10.1186/1471-2407-10-402. PMID: 20678220. PMCID: PMC2920883.

3. Юркштович Т.Л., Голуб Н.В., Костерова Р.И., Алиновская В. А. Фосфаты крахмала и декстрана: получение и возможность использования в медицинских целях. Тезисы доклада на XXIII Международной научно-технической конференции «Химические реак тивы, реагенты и процессы малотоннажной химии», 27-29 октября 2010 г. Минск, 2010. С. 42.

4. Bespalov V.G., Belyaeva О.А., Kireeva G.S. et al. Dioxadet and Cisplatin Anti-Tumor Activity Increase in Hyperthermic Intraperitoneal Chemoperfusion on Advanced Ovarian Carcinoma Model. J Modern Technologies in Medicine ser Biomed Invest 2014;6(4):48-52.

5. Самченко Ю.М., Ульберг З.Р. Специфические взаимодействия полиэлектролитных гидрогелей с антиглаукомными лекарственными средствами. Коллоидный журнал 1996;58(2):240-3.

6. Трещалина Е.М., Жукова О.С., Герасимова Г.К. и др. Методические указания по изучению противоопухолевой активности фармакологических веществ. В кн.: Руководство по экспериментальному (доклиническому) изучению новых фармакологических веществ. Под общей ред. Р.У. Хабриева. 2-е изд. М.: Медицина, 2005. С. 637-651.

7. Bate S.T., Clark R.A. The Design and Statistical Analysis of Animal Experiments. Cambridge University Press 2014:234-7.

8. Festing M.F. W., Altman D.G. Guidelines for the Design and Statistical Analysis of Experiments Using Laboratory Animals. ILAR J 2002;43(4):244-58.

9. Therneau T., Grambsch P. Modeling Survival Data: Extending the Cox Model. Springer-Verlag, 2000. 350 p.

10. R Core Team (2014). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, URL: http://www.R-project.org/. Date of access: 01.11.2014.

11. Давыдов М.И., Тер-Ованесов М.Д., Буйденок Ю.В. и др. Гипертермическая интраоперационная интраперитонеальная химиотерапия при раке желудка: существует ли реальная возможность изменить прогноз?