Zhurikov , R., Kovalenko, L., Alexeeva, S., Nikitin, S., & Durnev, A. (2023). The effect of 5-hydroxypyrimidine derivatives on the antitumor effect of gemcitabine, hematological parameters, and survival of mice with adenocarcinoma Ca755. Voprosy Onkologii, 69(2), 238–245. https://doi.org/10.37469/0507-3758-2023-69-2-238-245

Abstract

Introduction. The combined use of cytostatic agents with drugs from other groups is a promising method for reducing hematotoxicity.

Aim. To evaluate the impact of 5-hydroxypyrimidine derivatives and gemcitabine, as well as their combinations, on tumor growth inhibition, survival, and hematological parameters in animals with Ca755 adenocarcinoma.

Materials and methods. After inoculation of adenocarcinoma Ca755 mice received SNK-411, SNK-578, gemcitabine or their combination from 2nd to 15th day of tumor development. Tumor volume was measured and tumor growth inhibition was calculated on the 9th, 16th and 21st days of tumor development. On the 22nd day, half of the animals were left for follow-up and evaluation of survival, while the other half was euthanized, and their blood samples were taken for analysis.

Results. Compared to the intact control, a decrease in hemoglobin and erythrocyte levels was observed in all experimental active control groups that received SNK-411, SNK-578, and gemcitabine. The administration of 5-hydroxypyrimidine derivatives in combination with gemcitabine prevented the suppression of hematopoiesis. No statistically significant differences were found in platelet and leukocyte counts among the groups. Tumor growth inhibition (TGI) was studied on 7th day after the 14-day administration of SNK-411. In the group that received SNK-411 TGI was 45 %, in the group that received SNK-578 — 53%, in the group treated by gemcitabine — 61 %. 14-day combined administration of SNK-411 and gemcitabine resulted in 79 % TGI. Combination of SNK-578 and gemcitabine inhibited tumor growth by 80 %. Gemcitabine increased median survival time (MST) by 44 %, SNK-411 — by 18 %, SNK-578 — by 21 %. Combinations of SNK-411 and gemcitabine increased MST by 62 %, SNK-578 and gemcitabine — by 71 %.

Conclusion. The combination of gemcitabine and 5-hydroxypyrimidine derivatives demonstrated prominent antitumor effect without hematotoxicity.

https://doi.org/10.37469/0507-3758-2023-69-2-238-245

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References

Radziwon P, Krzakowski M, Kalinka E, et all. Anemia in cancer patients – Expert group recommendations. Revision 2020. Oncol Clin Pract. 2020;16(5):261269. doi:10.5603/OCP.2020.0020.

Busti F, Marchi G, Ugolini S, et al. Anemia and iron deficiency in cancer patients: role of iron replacement therapy. Pharmaceuticals. 2018;11(4):94110. doi:10.3390/ph11040094.

Mokhtari RB, Homayouni TS, Baluch N, et al. Combination therapy in combating cancer. Oncotarget. 2017;8(23):3802238043 doi:10.18632/oncotarget.16723.

Коваленко Л.П., Никитин С.В., Сорокина А.В. и др. Влияние 2-изобутил-4,6- диметил-5-оксипиримидина на рост и метастазирование карциномы легкого lewis у мышей линии C57Bl/6. Эксп. клин. фармакология. 2020;83(6):2427 [Kovalenko LP, Nikitin SV, Sorokina AV, et al. Effect of 2-isobutyl-4,6-dimethyl-5-oxypyrimidine on growth and metastasis of Lewis lung carcinoma in C57BL/6 mice. Experimental and clinical pharmacology. 2020;83(6):2427 (In Russ.)]. doi:10.30906/0869-2092-2020-83-1-24-27.

Nikitin SV, Rebeko AG, Zhurikov RV, et al. Synthesis and antitumor and antimetastatic activity of 5-hydroxypyrimidine derivatives. Pharmaceutical Chemistry Journal. 2019;53 (8):697700. doi:10.1007/s11094-019-02065-1.

Коваленко Л.П., Коржова К.В., Никитин С.В. Противоаллергенная и противовоспалительная активность производных 5-оксипиримидина (СНК-411 и СНК-578). Эксп. клин. фармакология. 2020;83(10):912 [Kovalenko LP, Korzhova KV, Nikitin SV. Antiallergenic and anti-inflammatory activity of 5-oxypirimidine. Experimental and clinical pharmacology. 2020;83(10):912 (In Russ.)]. doi:10.30906/0869-2092-2020-83-10-9-12.

Студенцов Е.П., Рамш С.М., Казурова Е.Г. и др. Адаптогены и родственные группы лекарственных препаратов – 50 лет поисков. Обзоры по клин. фарм. и лек. терапии. 2013;11(4):343 [Studentsov EP, Ramsh SM, Kazurova EG, et al. Adaptogens and similar groups of drugs – 50 years of search. Reviews of clinical pharmacology and drug therapy. 2013;11(4):343 (In Russ.)]. doi:10.17816/RCF1143-43.

Семиглазова Т.Ю., Гершанович М.Л., Латипова Д.Х. и др. Эффективность низких доз гемцитабина в комбинации с цисплатином в лечение диссеминированного рака молочной железы с прогрессированием после применения антрациклинов, таксанов и капецитабина. Фарматека. 2012;(8):6166 [Semiglazova TU, Gershanovich ML, Latipova DH, et al. Efficacy of low-dose gemcitabine in combination with cisplatin for therapy of disseminated mammary gland carcinoma with progression after combination of anthracyclines, taxans and capecitabin. Pharmateka. 2012;(8):6166 (In Russ.)].

Locker GJ, Wenzel C, Schmidinger M, et al. Unexpected severe myelotoxicity of gemcitabine in pretreated breast cancer patients. Anticancer drugs. 2001;12(3):20912. doi:10.1097/00001813-200103000-00006.

Масягин В.А., Сипров А.В., Волкова Н.Д. и др. Сравнительная оценка гематопротекторной эффективности производных пиримидина и 3-гидроксипиридина при противоопухолевой химиотерапии в эксперименте. Современные проблемы науки и образования. 2015;3 [Masyagin VA, Siprov AV, Volkova ND, et al. Comparative analysis of hematoprotective effects of 3-hydroxypyrimidine and pyrimidine derivatives for anticancer therapy in experiment. Contemporary Problems of Science And Education. 2015;3 (In Russ.)].

Соловьева М.А., Сипров А.В., Агеев В.П. и др. Влияние производных пиримидина и 3-гидроксипиридина в составе липосом на показатели эритропоэза при использовании липосомальных доксорубицина и циклофосфамида у крыс со злокачественным опухолевым процессом. Современные проблемы науки и образования. 2021;2 [Solovyeva MA, Siprov AV, Ageev VP, et al. The effect of pyrimidine and 3-hydroxypyridine derivatives in liposomes on erythrocytopoiesis indicators in rats with malignant tumor process treated with liposomal doxorubicin and cyclophosphamide. Contemporary problems of science and education. 2021;2 (In Russ.)]. doi:10.17513/spno.30594.

Dicato M, Plawny L, Diedrich M. Anemia in cancer. Annals of oncology. 2010;7:vii167vii172. doi:10.1093/annonc/mdq284.

Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin. Cancer Biol. 2012;22:33–40. doi:10.1016/j.semcancer.2011.12.005.

Lan T, Chen L, Wei X. Inflammatory cytokines in cancer: comprehensive understanding and clinical progress in gene therapy. Cells. 2021;10(1):100118. doi:10.3390/cells10010100.

Кузнецова О.С., Таллерова А.В., Никитин С.В., Коваленко Л.П. Иммунофармакологические свойства нового производного 5-оксипиримидина СНК-411// Экспериментальная и клиническая фармакология 2015;78(4):69 [Kuznetsova OS, Tallerova AV, Nikitin SV, Kovalenko LP. Immunopharmacological activity of new 5-hydroxypirimidine derivative SNK-411. Experimental and clinical pharmacology. 2015;78(4):69 (In Russ.)]. doi:10.30906/0869-2092-2015-78-4-6-9.

Kuznetsova OS, Tallerova AV, Nikitin SV, et al. Effects of 5-pyrimidinol derivative snk-411 on cytokine profile of mice with lewis lung carcinoma. Bull Exp Biol Med. 2016;160(10):488491. doi:10.1007/s10517-016-3202-z.

Коваленко Л.П., Коржова К.В., Зайнуллина Л.Ф. и др. Влияние производных 5-оксипиримидина на рост опухоли и содержание цитокинов в сыворотке крови самок мышей линии СВА с раком шейки матки (РШМ-5). Биомедицинская химия. 2021;67(2):158161 [Kovalenko LP, Korzhova KV, Zainullina LF, et al. Effect of 5-hydroxypyrimidine derivatives on tumor growth and cytokine concentration in blood serum of female CBA mice with cervical cancer (RSHM-5). Biomeditsinskaya khimiya. 2021;67(2):158161 (In Russ.)]. doi:10.18097/pbmc20216702158.

Taniguchi K, Karina M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Seminars in Immunology. 2014;26(1):54–74. doi:10.1016/j.smim.2014.01.001.

Wang H, Joyce J. Alternative activation of tumor-associated macrophages by IL-4. Priming for protumoral functions. Cell Cycle. 2010;9(24):48244835. doi:10.4161/cc.9.24.14322.

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