Value of rationality cisplatin addition into prospidin hydrogel for intraperitoneal chemotherapy of Zajdel hepatoma

Introduction. Earlier it has been shown that the hydrogel (HG) on the basis of the dextran phosphate (DP) increases effectivity of cisplatin (CDDP) and especially prospidin (Pr) which at intraperitoneal (i.p.) therapy of the rat Zajdel ascite hepatoma (ZAH) the long-lived the complete remission (CR) of an ascites. It was assumpte that addition of the CDDP to HG/Pr with receiving double composition (HG/ Pr/CDDP) can lead to increase its efficacy. The purpose of research - the assessment of a possibility to increasing of efficacy i.p. therapy of an ZAH by the HG with Pr and CDDP. Materials and methods. It was used 55 white outbreed rats with ZAH (n = 7-10) by which obtained i.p. single therapy with HG/Pr/ CDDP in doses for Pr of 250 or 500 mg/kg and for CDDP of 3.0 of 5.5 mg/kg. Groups of comparison received HG/Pr in adequate doses. For assessment of effectivity the most significant index - number of the CR on accumulation of an ascites (control time - 42 days) with assessment of decrease in the relative risk (Cox model of proportional risks) and cumulative survival was chosen. Results. It is shown that efficacy of HG/Pr/CDDP when Pr was used in maximal doses of500 mg/kg was equal to HG/Pr, CR = 100 % against this model. When it was used Pr with subtherapeutic dose of 250 mg/kg CR = 0, but addition of the HG/CDDP led to CR = 50-70 % with depended on dose, and simultaneously with increase in cumulative survival up to p_{l mk} = 0,004. The good tolerance of all therapeutic systems was evaluated. Conclusion. In rats with ZAH, a double composition of HG/Pr/CDDP in a high therapeutic dose for Pr of500 mg/kg is equally effective with HG/Pr in dose of 500 mg/kg, which makes it impossible to evaluate the therapeutic gain of adding CDDP. At a subtherapeutic dose for Pr of 250 mg/kg, a double composition with CDDP provides CR in a part of the rats. The obtained data confirm the importance of HG/Pr for intraperitoneal therapy of tumoral lesions of the human abdominal cavity, for which HG/CDDP acts as an adjuvant.

гидрогелевая форма, цисплатин, проспидин, противоопухолевая активность, асцитная гепатома, prolonged hydrogel form, prospidin, cisplatin, antitumor activity, ascites hepatoma

1. Wang Y., Gong Ch., Yang L. et al. 5-FU-hydrogel inhibits colorectal peritoneal carcinomatosis and tumor growth in mice. BMC Cancer 2010;10(8):402. DOI: 10.1186/1471-2407-10-402. PMID: 20678220.

2. Ревтович М.Ю., Истомин Ю.П., Красько О.В. и др. Противоопухолевая активность гидрогелевой формы цисплатина на асцитной гепатоме Зайделя. Российский биотерапевтический журнал 2016;15(4):96-101. DOI: 10.17650/1726-9784-2016-15-4-97-102.

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

4. Konishi M., Tabata Y., Kariya M. et al. In vivo anti-tumor effect though the controlled release of cisplatin from biodegrad able gelatin hydrogel. J Control Release 2003;92(3):301-13. PMID: 14568411.

5. Hyoudou K., Nishikawa M., Ikemura M. et al. Cationized catalase-loaded hydrogel for growth inhibition of peritoneally disseminated tumor cells. J Control Release 2007;122(2):151-8. PMID: 17651858.

6. Van Tomme S.R., Hennink W.E. Biodegradable dextran hydrogels for protein delivery applications. Expert Rev Med Devices 2007;4(2):147-64. DOI: 10.1586/17434440.4.2.147. PMID: 17359222.

7. Ревтович М.Ю., Бычковский П.М., Красько О.В. и др. Интраперитонеальная химиотерапия полимер-иммобилизованной формой проспидина асцитной гепатомы Зайделя. Вестник БГУ (серия 2) 2015;2:29-37.

8. Бычковский П.М., Юркштович Т.Л., Голуб Н.В. и др. Получение и противоопухолевая активность гелеобразующего препарата проспидина. Химико-фармацевтический журнал 2013;47(4):107-12.

9. Трещалина Е.М., Жукова О.С., Герасимова Г.К. и др. Методические рекомендации по доклиническому изучению противоопухолевой активности лекарственных средств. В кн.: Руководство по проведению доклинических исследований лекарственных средств. Часть первая. М.: Гриф и К, 2012. С. 642-657.

10. Bate S.T., Clark RA. The design and statistical analysis of animal experiments. Cambridge: University Press, 2014. Pp. 234-237.

11. 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. DOI: 10.1093/ilar.43.4.244. PMID: 12391400.

12. Therneau T., Grambsch P. Modeling survival data: extending the Cox model. New York: Springer-Verlag, 2000. 350 p.

13. 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/ (last access date 01.11.2014).