Dynamics of morphological changes in the heart of rats after serial systemic administration of Doxorubicin

  • O.H. Kostiuk National Pirogov Memorial Medical University, Vinnytsya, Ukraine
  • N.L. Hodovan National Pirogov Memorial Medical University, Vinnytsya, Ukraine
  • P.P. Gormash Utility non-profit enterprise “Vinnitsa Regional Pathological Bureau of Vinnitsa Regional Council”, Vinnytsya, Ukraine
  • I.V. Taran National Pirogov Memorial Medical University, Vinnytsya, Ukraine
  • D.I. Grebeniuk National Pirogov Memorial Medical University, Vinnytsya, Ukraine
  • O.V. Mashevska National Pirogov Memorial Medical University, Vinnytsya, Ukraine
Keywords: Doxorubicin, cardiomyopathy, morphology, experiment, rats.


Along with a good antitumor effect, Doxorubicin has a systemic effect with damage to vital organs, in particular the heart. The lack of a unified approach to dosing and the frequency of administration of Doxorubicin in the experiment prompts the search for an optimal model of Doxorubicin cardiomyopathy. The aim of the study was to develop a method of serial administration of Doxorubicin in medium therapeutic doses in an experiment and to evaluate the cardiotoxic effect of the drug. 42 female Wistar rats were included in the study. The control group consisted of 7 intact rats. The experimental group consisted of 35 rats who received systemic chemotherapy with Doxorubicin at a dose of 5 mg/kg once a week for 5 weeks. On days 7th, 14th, 21st, 28th, 35th, the hearts of experimental animals were taken for morphological examination. Histomorphometrically determined: the diameter of cardiomyocytes (in the middle part) and the transverse diameter of their nucleus, the width of the interstitial space (endo- and perimysia). The data of histomorphological and histomorphometric examination of the myocardium testified that all animals of the experimental group had a circulatory disorder in the heart muscle at the level of hemomicrocirculation. Such changes led to cardiomyocyte hypotrophy, interstitial edema and fibrosis. During systemic chemotherapy, the animals showed marked changes in the myocardium, such as expansion of the endomysial zone, due to capillary congestion and edema, in comparison with animals of the intact group. At the end of the experiment, the animals of the experimental group retained the expansion of the endomysial zone, mainly due to interstitial fibrosis. Such changes indicate myocardial hypoxemia with damage and death of cardiomyocytes, activation of interstitial and replacement collagen formation. The obtained morphological data indicate the development of dilated cardiomyopathy in experimental animals. Serial intraperitoneal administration of Doxorubicin at a dose of 5 mg/kg once a week for 5 weeks causes morphological changes in the myocardium of experimental animals, similar to changes in the heart of people undergoing chemotherapy with this drug.


[1] Akazawa, H. (2017). Cardiotoxicity of Cancer Chemotherapy - Mechanisms and Therapeutic Approach. Gan to kagaku ryoho. Cancer & chemotherapy, 44(13), 2058-2063. Pubmed: 29361617

[2] Al-Malky, H. S., Al Harthi, S. E., & Osman, A. M. (2020). Major obstacles to doxorubicin therapy: Cardiotoxicity and drug resistance. Journal of Oncology Pharmacy Practice: official publication of the International Society of Oncology Pharmacy Practitioners, 26(2), 434-444. https://doi.org/10.1177/1078155219877931

[3] Aygun, H., & Gul, S. S. (2019). Cardioprotective effect of melatonin and agomelatine on doxorubicin-induced cardiotoxicity in a rat model: an electrocardiographic, scintigraphic and biochemical study. Bratislavske Lekarske Listy, 120(4), 249-255. https://doi.org/10.4149/BLL_2019_045

[4] Babiker, H. M., McBride, A., Newton, M., Boehmer, L. M., Drucker, A. G., Gowan, M. … Hollands, J. M. (2018). Cardiotoxic effects of chemotherapy: A review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system. Critical Reviews in Oncology/Hematology, 126, 186-200. https://doi.org/10.1016/j.critrevonc.2018.03.014

[4] Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a Cancer Journal for Clinicians, 68(6), 394-424. https://doi.org/10.3322/caac.21492

[5] Del Pozo, J. G., Herranz, A. F., Arranz, A. J. A., Rodríguez, F. E., Subirá, R. D., Lledó, G. E. … Hernández, F. C. (2020). Effect of adjuvant chemotherapy in locally advanced urothelial carcinoma of the bladder treated with cystectomy. Efecto de la quimioterapia adyuvante en el carcinoma urotelial de vejiga localmente avanzado tratado con cistectomía. Actas Urologicas Espanolas, 44(2), 94-102. https://doi.org/10.1016/j.acuro.2019.08.009

[6] Diamanti, J., Mezzetti, B., Giampieri, F., Alvarez-Suarez, J. M., Quiles, J. L., Gonzalez-Alonso, A. … Battino, M. (2014). Doxorubicin-induced oxidative stress in rats is efficiently counteracted by dietary anthocyanin differently enriched strawberry (Fragaria × ananassa Duch.). Journal of Agricultural and Food Chemistry, 62(18), 3935-3943. https://doi.org/10.1021/jf405721d

[7] Elies, A., Rivière, S., Pouget, N., Becette, V., Dubot, C., Donnadieu, A. … Bonneau, C. (2018). The role of neoadjuvant chemotherapy in ovarian cancer. Expert Review of Anticancer Therapy, 18(6), 555-566. https://doi.org/10.1080/14737140.2018.1458614

[8] Fujiwara, K. (2020). Gynecologic Cancer Chemotherapy for Gynecologic Cancer 2020. Gan To Kagaku Ryoho, 47(2), 232. PMID: 32381953.

[9] Huguet, F., Schick, U., & Pointreau, Y. (2017). Place de la chimiothérapie d’induction dans le traitement des carcinomes épidermoïdes des voies aérodigestives supérieures : contre [Role of induction chemotherapy in head and neck cancer: Cons]. Cancer Radiotherapie:Journal de la Societe Francaise de Radiotherapie Oncologique, 21(6-7), 510-514. https://doi.org/10.1016/j.canrad.2017.07.020

[10] Ikegame, K., & Terashima, M. (2020). Perioperative Chemotherapy for Gastric Cancer. Gan To Kagaku Ryoho, 47(4), 569-573.

[11] Jain, D., & Aronow, W. (2019). Cardiotoxicity of cancer chemotherapy in clinical practice. Hospital Practice (1995), 47(1), 6-15. https://doi.org/10.1080/21548331.2018.1530831

[12] Kang, Y., Wang, W., Zhao, H., Qiao, Z., Shen, X., & He, B. (2017). Assessment of Subclinical Doxorubicin-induced Cardiotoxicity in a Rat Model by Speckle-Tracking Imaging. Arquivos Brasileiros de Cardiologia, 109(2). https://doi.org/10.5935/abc.20170097

[13] Koleini, N., & Kardami, E. (2017). Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity. Oncotarget, 28(8), 46663-46680. https://doi.org/10.18632/oncotarget.16944

[14] Lehmann, L. H., & Fröhling, S. (2020). Mechanismen der Kardiotoxizität onkologischer Therapien [Mechanisms of cardiotoxicity of oncological therapies]. Der Internist, 61(11), 1132-1139. https://doi.org/10.1007/s00108-020-00881-2

[15] Liu, G. F., Li, G. J., & Zhao, H. (2018). Efficacy and Toxicity of Different Chemotherapy Regimens in the Treatment of Advanced or Metastatic Pancreatic Cancer: A Network Meta-Analysis. Journal of Cellular Biochemistry, 119(1), 511–523. https://doi.org/10.1002/jcb.26210

[16] Mandziuk, S., Gieroba, R., Korga, A., Matysiak, W., Jodlowska-Jedrych, B., Burdan, F. … Dudka, J. (2015). The differential effects of green tea on dose-dependent doxorubicin toxicity. Food & Nutrition Research, 59, 29754. https://doi.org/10.3402/fnr.v59.29754

[17] Miller, K. D., Nogueira, L., Mariotto, A. B., Rowland, J. H., Yabroff, K. R., Alfano, C. M. … Siegel, R. L. (2019). Cancer treatment and survivorship statistics, 2019. CA: a Cancer Journal for Clinicians, 69(5), 363-385. https://doi.org/10.3322/caac.21565

[18] Nair, A. B., & Jacob, S. (2016). A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy, 7(2), 27-31. https://doi.org/10.4103/0976-0105.177703

[19] Pugazhendhi, A., Edison, T., Velmurugan, B. K., Jacob, J. A., & Karuppusamy, I. (2018). Toxicity of Doxorubicin (Dox) to different experimental organ systems. Life Sciences, 200, 26-30. https://doi.org/10.1016/j.lfs.2018.03.023

[20] Renu, K., Abilash, V. G., Pichiah, T. P. B., & Arunachalam, S. (2018). Molecular mechanism of Doxorubicin-induced cardiomyopathy – An update. European Journal of Pharmacology, 818, 241-253. https://doi.org/10.1016/j.ejphar.2017.10.043

[21] Rosati, G., & Fé, A. (2020). Prolonged clinical response with regorafenib administered as second-line therapy in an elderly patient suffering from peritoneal carcinomatosis of colon cancer. Journal of Chemotherapy (Florence, Italy), 1-6. Advance online publication. https://doi.org/10.1080/1120009X.2020.1866823

[22] Saeki, T. (2020). Breast and Endocrine Tumor Role of the Oral 5-FU in Adjuvant Setting for Brest Cancer. Gan to kagaku ryoho. Cancer & chemotherapy, 47(12), 1672. PMID: 33342980

[23] Sun, X. P., Wan, L. L., Yang, Q. J., Huo, Y., Han, Y. L., & Guo, C. (2017). Scutellarin protects against doxorubicin-induced acute cardiotoxicity and regulates its accumulation in the heart. Archives of Pharmacal Research, 40(7), 875-883. https://doi.org/10.1007/s12272-017-0907-0

[24] van der Zanden, S. Y., Qiao, X., & Neefjes, J. (2020). New insights into the activities and toxicities of the old anticancer drug doxorubicin. The FEBS Journal, 10.1111/febs.15583. Advance online publication. https://doi.org/10.1111/febs.15583

[25] Xu, A., Deng, F., Chen, Y., Kong, Y., Pan, L., Liao, Q. … Sheng, X. (2020). NF-κB pathway activation during endothelial-to-mesenchymal transition in a rat model of doxorubicin-induced cardiotoxicity. Biomed. Pharmacother., 130, 110-525. doi: 10.1016/j.biopha.2020.110525

[26] Yasui, H. (2016). Safe Handling of Cancer Chemotherapy Drugs. Gan to kagaku ryoho. Cancer & chemotherapy, 43(5), 503-508. PMID: 27210078.

[27] Zhang, J., Cui, L., Han, X., Zhang, Y., Zhang, X., Chu, X. … Chu, L. (2017). Protective effects of tannic acid on acute doxorubicin-induced cardiotoxicity: Involvement of suppression in oxidative stress, inflammation, and apoptosis. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 93, 1253-1260. https://doi.org/10.1016/j.biopha.2017.07.051
How to Cite
Kostiuk, O., Hodovan, N., Gormash, P., Taran, I., Grebeniuk, D., & Mashevska, O. (2020). Dynamics of morphological changes in the heart of rats after serial systemic administration of Doxorubicin. Reports of Morphology, 26(4), 22-29. https://doi.org/https://doi.org/10.31393/morphology-journal-2020-26(4)-04