Роль доксорубицина в формировании кардиотоксичности – консенсусное заявление. Часть II. Кардиотоксичность доксорубицина, не связанная с миоцитами, и стратегия кардиопротекции (обзор)

Введение. Применение доксорубицина в клинической практике сопровождается кумулятивным и дозозависимым токсическим воздействием на кардиомиоциты, приводящим к увеличению риска смертности среди пациентов с онкологическими заболеваниями и, как следствие, возникновению ограничений в отношении его применения.

Текст. Опасной нежелательной реакцией доксорубицина является кардиомиопатия, приводящая к застойной сердечной недостаточности. В основе кардиотоксичности лежат как минимум несколько патофизиологических механизмов (детальнее описанных в первой части обзора), приводящих к повреждению кардиомиоцитов в результате окислительного стресса с образованием свободных радикалов, нарушения функции митохондрий, аутофагии, высвобождения оксида азота и медиаторов воспаления, а также изменения экспрессии генов и белков, что приводит к апоптозу. В текущей (второй) части обзора представлена подробная информация о современном понимании патофизиологических механизмов, лежащих в основе уже описанной кардиотоксичности, и влияния доксорубицина на другие клетки сердца. Использование кардиопротективных стратегий позволит снизить выраженность и вероятность развития кардиотоксичности. В данной статье описаны стратегии, основанные на снижении максимальной кумулятивной дозы, изменении характера введения доксорубицина, использовании пегилированных липосомальных форм и кардиопротекстивных средств, а также физических нагрузок.

Заключение. Несмотря на огромное количество научных работ, посвященных различным аспектам кардиотоксичности доксорубицина, ее профилактики и лечения, данный вопрос требует более тщательного изучения и выработки более совершенных методов ранней диагностики, профилактики и более эффективной терапии этого осложнения.

1. Andreev D. A., Balakin E. I., Samoilov A. S., Pustovoit V. I. The Role of Doxorubicin in the Formation of Cardiotoxicity – Generally Accepted Statement. Part I. Prevalence and Mechanisms of Formation (Review). Drug development & registration. 2024;13(1):190–199. (In Russ.) DOI: 10.33380/2305-2066-2024-13-1-1508.

2. Wallace K. B., Sardão V. A., Oliveira P. J. Mitochondrial Determinants of Doxorubicin-Induced Cardiomyopathy. Circulation Research. 2020;126(7):926–941. DOI: 10.1161/CIRCRESAHA.119.314681.

3. Lefrak E. A., Pitha J., Rosenheim S., Gottlieb J. A. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer. 1973;32(2):302–314. DOI: 10.1002/1097-0142(197308)32:2<302::aid-cncr2820320205>3.0.co;2-2.

4. Swain S. M., Whaley F. S., Ewer M. S. Congestive heart failure in patients treated with doxorubicin. Cancer. 2003;97(11):2869–2879. DOI: 10.1002/cncr.11407.

5. Arai M., Yoguchi A., Takizawa T., Yokoyama T., Kanda T., Kurabayashi M., Nagai R. Mechanism of doxorubicin-induced inhibition of sarcoplasmic reticulum Ca²⁺-ATPase gene transcription. Circulation Research. 2000;86(1):8–14. DOI: 10.1161/01.res.86.1.8.

6. Steinherz L. J., Steinherz P. G., Tan C. T., Heller G., Murphy M. L. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA. 1991;266(12):1672–1677.

7. Maksjutov N. F., Murtazin A. A., Balakin E. I., Pustovoit V. I. Using machine learning approaches and omics technologies for assessment of human functional state. Modern Issues of Biomedicine. 2022;6(3). (In Russ.) DOI: 10.51871/2588-0500_2022_06_03_14.

8. Cardinale D., Colombo A., Bacchiani G., Tedeschi I., Meroni C. A., Veglia F., Civelli M., Lamantia G., Colombo N., Curigliano G., Fiorentini C., Cipolla C. M. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131(22):1981–1988. DOI: 10.1161/CIRCULATIONAHA.114.013777.

9. Pustovoit V. I., Balakin E. I., Maksjutov N. F., Murtazin A. A., Samoylov A. S. Change in the functional status of extreme athletes in response to adverse environmental conditions. Human sport medicine. 2022;22(S2):22–29. DOI: 10.14529/hsm22s203.

10. Jordan J. H., Castellino S. M., Meléndez G. C., Klepin H. D., Ellis L. R., Lamar Z., Vasu S., Kitzman D. W., Ntim W. O., Brubaker P. H., Reichek N., D’Agostino R. B., Hundley W. G. Left Ventricular Mass Change After Anthracycline Chemotherapy. Circulation: Heart Failure. 2018;11(7):e004560. DOI: 10.1161/CIRCHEARTFAILURE.117.004560.

11. Willis M. S., Parry T. L., Brown D. I., Mota R. I., Huang W., Beak J. Y., Sola M., Zhou C., Hicks S. T., Caughey M. C., D’Agostino R. B., Jordan J., Hundley W. G., Jensen B. C. Doxorubicin Exposure Causes Subacute Cardiac Atrophy Dependent on the Striated Muscle-Specific Ubiquitin Ligase MuRF1. Circulation: Heart Failure. 2019;12(3):e005234. DOI: 10.1161/CIRCHEARTFAILURE.118.005234.

12. Kajihara H., Yokozaki H., Yamahara M., Kadomoto Y., Tahara E. Anthracycline induced myocardial damage: An analysis of 16 autopsy cases. Pathology – Research and Practice. 1986;181(4):434–441. DOI: 10.1016/S0344-0338(86)80079-6.

13. Prezioso L., Tanzi S., Galaverna F., Frati C., Testa B., Savi M., Graiani G., Lagrasta C., Cavalli S., Galati S., Madeddu D., Rizzini E., Ferraro F., Musso E., Stilli D., Urbanek K., Piegari E., De Angelis A., Maseri A., Rossi F., Quaini E., Quaini F. Cancer Treatment-Induced Cardiotoxicity: a Cardiac Stem Cell Disease? Cardiovascular & Hematological Agents in Medicinal Chemistry. 2010;8(1):55–75. DOI: 10.2174/187152510790796165.

14. Bearzi C., Rota M., Hosoda T., Tillmanns J., Nascimbene A., De Angelis A., Yasuzawa-Amano S., Trofimova I., Siggins R. W., LeCapitaine N., Cascapera S., Beltrami A. P., D'Alessandro D. A., Zias E., Quaini F., Urbanek K., Michler R. E., Bolli R., Kajstura J., Leri A., Anversa P. Human cardiac stem cells. Proceedings of the National Academy of Sciences. 2007;104(35):14068–14073. DOI: 10.1073/pnas.0706760104.

15. Beltrami A. P., Barlucchi L., Torella D., Baker M., Limana F., Chimenti S., Kasahara H., Rota M., Musso E., Urbanek K., Leri A., Kajstura J., Nadal-Ginard B., Anversa P. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114(6):763–776. DOI: 10.1016/s0092-8674(03)00687-1.

16. Pfister O., Mouquet F., Jain M., Summer R., Helmes M., Fine A., Colucci W. S., Liao R. CD31^– but Not CD31⁺ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circulation Research. 2005;97(1):52–61. DOI: 10.1161/01.RES.0000173297.53793.fa.

17. Smith R. R., Barile L., Cho H. C., Leppo M. K., Hare J. M., Messina E., Giacomello A., Abraham M. R., Marbán E. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation. 2007;115(7):896–908. DOI: 10.1161/CIRCULATIONAHA.106.655209.

18. Cesselli D., Beltrami A. P., D’Aurizio F., Marcon P., Bergamin N., Toffoletto B., Pandolfi M., Puppato E., Marino L., Signore S., Livi U., Verardo R., Piazza S., Marchionni L., Fiorini C., Schneider C., Hosoda T., Rota M., Kajstura J., Anversa P., Beltrami C. A., Leri A. Effects of age and heart failure on human cardiac stem cell function. The American Journal of Pathology. 2011;179(1):349–366. DOI: 10.1016/j.ajpath.2011.03.036.

19. Chimenti C., Kajstura J., Torella D., Urbanek K., Heleniak H., Colussi C., Di Meglio F., Nadal-Ginard B., Frustaci A., Leri A., Maseri A., Anversa P. Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circulation Research. 2003;93(7):604–613. DOI: 10.1161/01.RES.0000093985.76901.AF.

20. Rota M., LeCapitaine N., Hosoda T., Boni A., De Angelis A., Padin-Iruegas M. E., Esposito G., Vitale S., Urbanek K., Casarsa C., Giorgio M., Lüscher T. F., Pelicci P. G., Anversa P., Leri A., Kajstura J. Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66 shc gene. Circulation Research. 2006;99(1):42–52. DOI: 10.1161/01.RES.0000231289.63468.08.

21. Rupp S., Bauer J., von Gerlach S., Fichtlscherer S., Zeiher A. M., Dimmeler S., Schranz D. Pressure overload leads to an increase of cardiac resident stem cells. Basic Research in Cardiology. 2012;107(2):252. DOI: 10.1007/s00395-012-0252-x.

22. Urbanek K., Torella D., Sheikh F., De Angelis A., Nurzynska D., Silvestri F., Beltrami C. A., Bussani R., Beltrami A. P., Quaini F., Bolli R., Leri A., Kajstura J., Anversa P. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proceedings of the National Academy of Sciences. 2005;102(24):8692–8697. DOI: 10.1073/pnas.0500169102.

23. Avolio E., Gianfranceschi G., Cesselli D., Caragnano A., Athanasakis E., Katare R., Meloni M., Palma A., Barchiesi A., Vascotto C., Toffoletto B., Mazzega E., Finato N., Aresu G., Livi U., Emanueli C., Scoles G., Beltrami C. A., Madeddu P., Beltrami A. P. Ex vivo molecular rejuvenation improves the therapeutic activity of senescent human cardiac stem cells in a mouse model of myocardial infarction. Stem Cells. 2014;32(9):2373–2385. DOI: 10.1002/stem.1728.

24. Kajstura J., Gurusamy N., Ogórek B., Goichberg P., Clavo-Rondon C., Hosoda T., D'Amario D., Bardelli S., Beltrami A. P., Cesselli D., Bussani R., del Monte F., Quaini F., Rota M., Beltrami C. A., Buchholz B. A., Leri A., Anversa P. Myocyte Turnover in the Aging Human Heart. Circulation Research. 2010;107(11):1374–1386. DOI: 10.1161/CIRCRESAHA.110.231498.

25. Huang C., Zhang X., Ramil J. M., Rikka S., Kim L., Lee Y., Gude N. A., Thistlethwaite P. A., Sussman M. A., Gottlieb R. A., Gustafsson Å. B. Juvenile exposure to anthracyclines impairs cardiac progenitor cell function and vascularization resulting in greater susceptibility to stress-induced myocardial injury in adult mice. Circulation. 2010;121(5):675–683. DOI: 10.1161/CIRCULATIONAHA.109.902221.

26. De Angelis A., Piegari E., Cappetta D., Marino L., Filippelli A., Berrino L., Ferreira-Martins J., Zheng H., Hosoda T., Rota M., Urbanek K., Kajstura J., Leri A., Rossi F., Anversa P. Anthracycline cardiomyopathy is mediated by depletion of the cardiac stem cell pool and is rescued by restoration of progenitor cell function. Circulation. 2010;121(2):276–292. DOI: 10.1161/CIRCULATIONAHA.109.895771.

27. Piegari E., De Angelis A., Cappetta D., Russo R., Esposito G., Costantino S., Graiani G., Frati C., Prezioso L., Berrino L., Urbanek K., Quaini F., Rossi F. Doxorubicin induces senescence and impairs function of human cardiac progenitor cells. Basic Research in Cardiology. 2013;108(2):334. DOI: 10.1007/s00395-013-0334-4.

28. De Angelis A., Piegari E., Cappetta D., Russo R., Esposito G., Ciuffreda L. P., Ferraiolo F. A. V., Frati C., Fagnoni F., Berrino L., Quaini F., Rossi F., Urbanek K. SIRT1 activation rescues doxorubicin-induced loss of functional competence of human cardiac progenitor cells. International Journal of Cardiology. 2015;189:30–44. DOI: 10.1016/j.ijcard.2015.03.438.

29. Piegari E., De Angelis A., Cappetta D., Russo R., Esposito G., Costantino S., Graiani G., Frati C., Prezioso L., Berrino L., Urbanek K., Quaini F., Rossi F. Doxorubicin induces senescence and impairs function of human cardiac progenitor cells. Basic Research in Cardiology. 2013;108(2):334. DOI: 10.1007/s00395-013-0334-4.

30. Cesselli D., Beltrami A. P., D’Aurizio F., Marcon P., Bergamin N., Toffoletto B., Pandolfi M., Puppato E., Marino L., Signore S., Livi U., Verardo R., Piazza S., Marchionni L., Fiorini C., Schneider C., Hosoda T., Rota M., Kajstura J., Anversa P., Beltrami C. A., Leri A. Effects of age and heart failure on human cardiac stem cell function. The American Journal of Pathology. 2011;179(1):349–366. DOI: 10.1016/j.ajpath.2011.03.036.

31. Linke A., Müller P., Nurzynska D., Casarsa C., Torella D., Nascimbene A., Castaldo C., Cascapera S., Böhm M., Quaini F., Urbanek K., Leri A., Hintze T. H., Kajstura J., Anversa P. Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proceedings of the National Academy of Sciences. 2005;102(25):8966–8971. DOI: 10.1073/pnas.0502678102.

32. Torella D., Rota M., Nurzynska D., Musso E., Monsen A., Shiraishi I., Zias E., Walsh K., Rosenzweig A., Sussman M. A., Urbanek K., Nadal-Ginard B., Kajstura J., Anversa P., Leri A. Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. Circulation Research. 2004;94(4):514–524. DOI: 10.1161/01.RES.0000117306.10142.50.

33. Urbanek K., Rota M., Cascapera S., Bearzi C., Nascimbene A., De Angelis A., Hosoda T., Chimenti S., Baker M., Limana F., Nurzynska D., Torella D., Rotatori F., Rastaldo R., Musso E., Quaini F., Leri A., Kajstura J., Anversa P. Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival. Circulation Research. 2005;97(7):663–673. DOI: 10.1161/01.RES.0000183733.53101.11.

34. Powell E. M., Mars W. M., Levitt P. Hepatocyte Growth Factor/Scatter Factor Is a Motogen for Interneurons Migrating from the Ventral to Dorsal Telencephalon. Neuron. 2001;30(1):79–89. DOI: 10.1016/S0896-6273(01)00264-1.

35. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005;120(4):513–522. DOI: 10.1016/j.cell.2005.02.003.

36. Beauséjour C. M., Krtolica A., Galimi F., Narita M., Lowe S. W., Yaswen P., Campisi J. Reversal of human cellular senescence: roles of the p53 and p16 pathways. The EMBO Journal. 2003;22(16):4212–4222. DOI: 10.1093/emboj/cdg417.

37. Takai H., Smogorzewska A., de Lange T. DNA damage foci at dysfunctional telomeres. Current Biology. 2003;13(17):1549–1556. DOI: 10.1016/s0960-9822(03)00542-6.

38. Ali M. K., Ewer M. S., Gibbs H. R., Swafford J., Graff K. L. Late doxorubicin-associated cardiotoxicity in children. Cancer. 1994;74(1):182–188. DOI: 10.1002/1097-0142(19940701)74:1<182::aid-cncr2820740129>3.0.co;2-2.

39. Chen M. H., Colan S. D., Diller L. Cardiovascular disease: cause of morbidity and mortality in adult survivors of childhood cancers. Circulation Research. 2011;108(5):619–628. DOI: 10.1161/CIRCRESAHA.110.224519.

40. Pai V. B., Nahata M. C. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Safety. 2000;22(4):263–302. DOI: 10.2165/00002018-200022040-00002.

41. Kuwahara F., Kai H., Tokuda K., Kai M., Takeshita A., Egashira K., Imaizumi T. Transforming growth Factor-β function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation. 2002;106(1):130–135. DOI: 10.1161/01.cir.0000020689.12472.e0.

42. Krstić J., Trivanović D., Mojsilović S., Santibanez J. F. Transforming Growth Factor-Beta and Oxidative Stress Interplay: Implications in Tumorigenesis and Cancer Progression. Oxidative Medicine and Cellular Longevity. 2015;2015:654594. DOI: 10.1155/2015/654594.

43. Li A.-H., Liu P. P., Villarreal F. J., Garcia R. A. Dynamic changes in myocardial matrix and relevance to disease: translational perspectives. Circulation Research. 2014;114(5):916–927. DOI: 10.1161/CIRCRESAHA.114.302819.

44. Cappetta D., Esposito G., Piegari E., Russo R., Ciuffreda L. P., Rivellino A., Berrino L., Rossi F., De Angelis A., Urbanek K. SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy. International Journal of Cardiology. 2016;205:99–110. DOI: 10.1016/j.ijcard.2015.12.008.

45. Urbanek K., Cesselli D., Rota M., Nascimbene A., De Angelis A., Hosoda T., Bearzi C., Boni A., Bolli R., Kajstura J., Anversa P., Leri A. Stem cell niches in the adult mouse heart. Proceedings of the National Academy of Sciences. 2006;103(24):9226–9231. DOI: 10.1073/pnas.0600635103.

46. Ramkisoensing A. A., de Vries A. A. F., Atsma D. E., Schalij M. J., Pijnappels D. A. Interaction between myofibroblasts and stem cells in the fibrotic heart: balancing between deterioration and regeneration. Cardiovascular Research. 2014;102(2):224–231. DOI: 10.1093/cvr/cvu047.

47. Soultati A., Mountzios G., Avgerinou C., Papaxoinis G., Pectasides D., Dimopoulos M.-A., Papadimitriou C. Endothelial vascular toxicity from chemotherapeutic agents: Preclinical evidence and clinical implications. Cancer Treatment Reviews. 2012;38(5):473–483. DOI: 10.1016/j.ctrv.2011.09.002.

48. Bielak-Zmijewska A., Wnuk M., Przybylska D., Grabowska W., Lewinska A., Alster O., Korwek Z., Cmoch A., Myszka A., Pikula S., Mosieniak G., Sikora E. A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta. Biogerontology. 2014;15(1):47–64. DOI: 10.1007/s10522-013-9477-9.

49. Murata T., Yamawaki H., Hori M., Sato K., Ozaki H., Karaki H. Chronic vascular toxicity of doxorubicin in an organ-cultured artery. British Journal of Pharmacology. 2001;132(7):1365–1373. DOI: 10.1038/sj.bjp.0703959.

50. Urbich C., Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circulation Research. 2004;95(4):343–353. DOI: 10.1161/01.RES.0000137877.89448.78.

51. Rafii S., Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nature Medicine. 2003;9(6):702–712. DOI: 10.1038/nm0603-702.

52. Hamed S., Barshack I., Luboshits G., Wexler D., Deutsch V., Keren G., George J. Erythropoietin improves myocardial performance in doxorubicin-induced cardiomyopathy. European Heart Journal. 2006;27(15):1876–1883. DOI: 10.1093/eurheartj/ehl044.

53. Takahashi T., Kalka C., Masuda H., Chen D., Silver M., Kearney M., Magner M., Isner J. M., Asahara T. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nature Medicine. 1999;5(4):434–438. DOI: 10.1038/7434.

54. Hill J. M., Zalos G., Halcox J. P. J., Schenke W. H., Waclawiw M. A., Quyyumi A. A., Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. New England Journal of Medicine. 2003;348(7):593–600. DOI: 10.1056/NEJMoa022287.

55. Maejima Y., Adachi S., Ito H., Hirao K., Isobe M. Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage. Aging Cell. 2008;7(2):125–136. DOI: 10.1111/j.1474-9726.2007.00358.x.

56. Spallarossa P., Altieri P., Barisione C., Passalacqua M., Aloi C., Fugazza G., Frassoni F., Podestà M., Canepa M., Ghigliotti G., Brunelli C. p38 MAPK and JNK antagonistically control senescence and cytoplasmic p16INK4A expression in doxorubicin-treated endothelial progenitor cells. PLoS ONE. 2010;5(12):e15583. DOI: 10.1371/journal.pone.0015583.

57. Wada T., Stepniak E., Hui L., Leibbrandt A., Katada T., Nishina H., Wagner E. F., Penninger J. M. Antagonistic control of cell fates by JNK and p38-MAPK signaling. Cell Death & Differentiation. 2008;15(1):89–93. DOI: 10.1038/sj.cdd.4402222.

58. Spallarossa P., Altieri P., Pronzato P., Aloi C., Ghigliotti G., Barsotti A., Brunelli C. Sublethal doses of an anti-erbB2 antibody leads to death by apoptosis in cardiomyocytes sensitized by low prosenescent doses of epirubicin: the protective role of dexrazoxane. Journal of Pharmacology and Experimental Therapeutics. 2010;332(1):87–96. DOI: 10.1124/jpet.109.159525.

59. Yasuda K., Park H.-C., Ratliff B., Addabbo F., Hatzopoulos A. K., Chander P., Goligorsky M. S. Adriamycin nephropathy: a failure of endothelial progenitor cell-induced repair. The American Journal of Pathology. 2010;176(4):1685–1695. DOI: 10.2353/ajpath.2010.091071.

60. Moore M. A. S., Hattori K., Heissig B., Shieh J.-H., Dias S., Crystal R. G., Rafii S. Mobilization of endothelial and hematopoietic stem and progenitor cells by adenovector-mediated elevation of serum levels of SDF-1, VEGF, and angiopoietin-1. Annals of the New York Academy of Sciences. 2001;938(1):36–47. DOI: 10.1111/j.1749-6632.2001.tb03572.x.

61. McNiece I. K., Briddell R. A., Hartley C. A., Smith K. A., Andrews R. G. Stem cell factor enhances in vivo effects of granulocyte colony stimulating factor for stimulating mobilization of peripheral blood progenitor cells. STEM CELLS. 1993;11(S2):36–41. DOI: 10.1002/stem.5530110807.

62. Quaini F., Urbanek K., Beltrami A. P., Finato N., Beltrami C. A., Nadal-Ginard B., Kajstura J., Leri A., Anversa P. Chimerism of the transplanted heart. New England Journal of Medicine. 2002;346(1):5–15. DOI: 10.1056/NEJMoa012081.

63. Thiele J., Varus E., Wickenhauser C., Kvasnicka H. M., Metz K. A., Beelen D. W. Regeneration of heart muscle tissue: quantification of chimeric cardiomyocytes and endothelial cells following transplantation. Histol Histopathol. 2004;19(1):201–209. DOI: 10.14670/HH-19.201.

64. Fukuhara S., Tomita S., Nakatani T., Ohtsu Y., Ishida M., Yutani C., Kitamura S. G-CSF promotes bone marrow cells to migrate into infarcted mice heart, and differentiate into cardiomyocytes. Cell Transplantation. 2004;13(7–8):741–748. DOI: 10.3727/000000004783983486.

65. Tomita S., Ishida M., Nakatani T., Fukuhara S., Hisashi Y., Ohtsu Y., Suga M., Yutani C., Yagihara T., Yamada K., Kitamura S. Bone marrow is a source of regenerated cardiomyocytes in doxorubicin-induced cardiomyopathy and granulocyte colony-stimulating factor enhances migration of bone marrow cells and attenuates cardiotoxicity of doxorubicin under electron microscopy. The Journal of Heart and Lung Transplantation. 2004;23(5):577–584. DOI: 10.1016/j.healun.2003.06.001.

66. Urbanek K., Frati C., Graiani G., Madeddu D., Falco A., Cavalli S., Lorusso B., Gervasi A., Prezioso L., Savi M., Ferraro F., Galaverna F., Rossetti P., Lagrasta C., Re F., Quaini E., Rossi F., Angelis A., Quaini F. Cardioprotection by Targeting the Pool of Resident and Extracardiac Progenitors. Current Drug Targets. 2015;16(8):884–894. DOI: 10.2174/1389450116666150126105002.

67. Yang F., Chen H., Liu Y., Yin K., Wang Y., Li X., Wang G., Wang S., Tan X., Xu C., Lu Y., Cai B. Doxorubicin caused apoptosis of mesenchymal stem cells via p38, JNK and p53 pathway. Cellular Physiology and Biochemistry. 2013;32(4):1072–1082. DOI: 10.1159/000354507.

68. Oliveira M. S., Carvalho J. L., De Angelis Campos A. C., Gomes D. A., de Goes A. M., Melo M. M. Doxorubicin has in vivo toxicological effects on ex vivo cultured mesenchymal stem cells. Toxicology Letters. 2014;224(3):380–386. DOI: 10.1016/j.toxlet.2013.11.023.

69. Lipshultz S. E., Lipsitz S. R., Sallan S. E., Dalton V. M., Mone S. M., Gelber R. D., Colan S. D. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. Journal of Clinical Oncology. 2005;23(12):2629–2636. DOI: 10.1200/JCO.2005.12.121.

70. Legha S. S., Benjamin R. S., Mackay B., Yap H. Y., Wallace S., Ewer M., Blumenschein G. R., Freireich E. J. Adriamycin therapy by continuous intravenous infusion in patients with metastatic breast cancer. Cancer. 1982;49(9):1762–1766. DOI: 10.1002/1097-0142(19820501)49:9<1762::aid-cncr2820490905>3.0.co;2-q.

71. Batist G. Cardiac safety of liposomal anthracyclines. Cardiovascular Toxicology. 2007;7(2):72–74. DOI: 10.1007/s12012-007-0014-4.

72. Van Dalen E. C., Michiels E. M. C., Caron H. N., Kremer L. C. M. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database of Systematic Reviews. 2010;(3):CD005006. DOI: 10.1002/14651858.CD005006.pub3.

73. Lipshultz S. E., Scully R. E., Lipsitz S. R., Sallan S. E., Silverman L. B., Miller T. L., Barry E. V., Asselin B. L., Athale U., Clavell L. A., Larsen E., Moghrabi A., Samson Y., Michon B., Schorin M. A., Cohen H. J., Neuberg D. S., Orav E. J., Colan S. D. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. The Lancet Oncology. 2010;11(10):950–961. DOI: 10.1016/S1470-2045(10)70204-7.

74. Speyer J. L., Green M. D., Zeleniuch-Jacquotte A., Wernz J. C., Rey M., Sanger J., Kramer E., Ferrans V., Hochster H., Meyers M. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. Journal of Clinical Oncology. 1992;10(1):117–127. DOI: 10.1200/JCO.1992.10.1.117.

75. Hochster H. S. Clinical pharmacology of dexrazoxane. Seminars in Oncology. 1998;25(4 Suppl 10):37–42.

76. Lyu Y. L., Kerrigan J. E., Lin C.-P., Azarova A. M., Tsai Y.-C., Ban Y., Liu L. F. Topoisomerase IIβ–Mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Research. 2007;67(18):8839–8846. DOI: 10.1158/0008-5472.CAN-07-1649.

77. Ladas E. J., Jacobson J. S., Kennedy D. D., Teel K., Fleischauer A., Kelly K. M. Antioxidants and cancer therapy: a systematic review. Journal of Clinical Oncology. 2004;22(3):517–528. DOI: 10.1200/JCO.2004.03.086.

78. Kalay N., Basar E., Ozdogru I., Er O., Cetinkaya Y., Dogan A., Oguzhan A., Eryol N. K., Topsakal R., Ergin A., Inanc T. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. Journal of the American College of Cardiology. 2006;48(11):2258–2262. DOI: 10.1016/j.jacc.2006.07.052.

79. Kaya M. G., Ozkan M., Gunebakmaz O., Akkaya H., Kaya E. G., Akpek M., Kalay N., Dikilitas M., Yarlioglues M., Karaca H., Berk V., Ardic I., Ergin A., Lam Y. Y. Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. International Journal of Cardiology. 2013;167(5):2306–2310. DOI: 10.1016/j.ijcard.2012.06.023.

80. Spallarossa P., Garibaldi S., Altieri P., Fabbi P., Manca V., Nasti S., Rossettin P., Ghigliotti G., Ballestrero A., Patrone F. Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro. Journal of Molecular and Cellular Cardiology. 2004;37(4):837–846. DOI: 10.1016/j.yjmcc.2004.05.024.

81. Mason R. P., Kalinowski L., Jacob R. F., Jacoby A. M., Malinski T. Nebivolol reduces nitroxidative stress and restores nitric oxide bioavailability in endothelium of black Americans. Circulation. 2005;112(24):3795–3801. DOI: 10.1161/CIRCULATIONAHA.105.556233.

82. Singal P., Li T., Kumar D., Danelisen I., Iliskovic N. Adriamycin-induced heart failure: mechanism and modulation. Molecular and Cellular Biochemistry. 2000;207(1–2):77–86. DOI: 10.1023/a:1007094214460.

83. Ascensão A., Magalhães J., Soares J. M. C., Ferreira R., Neuparth M. J., Marques F., Oliveira P. J., Duarte J. A. Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis. American Journal of Physiology-Heart and Circulatory Physiology. 2005;289(2):H722–H731. DOI: 10.1152/ajpheart.01249.2004.

84. Foote K., Reinhold J., Yu E. P. K., Figg N. L., Finigan A., Murphy M. P., Bennett M. R. Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice. Aging Cell. 2018;17(4):e12773. DOI: 10.1111/acel.12773.

85. Yue P., Jing S., Liu L., Ma F., Zhang Y., Wang C., Duan H., Zhou K., Hua Y., Wu G., Li Y. Association between mitochondrial DNA copy number and cardiovascular disease: Current evidence based on a systematic review and meta-analysis. PLOS ONE. 2018;13(11):e0206003. DOI: 10.1371/journal.pone.0206003.

86. Pustovoit V. I. Database of methods for complex nutritional-metabolic correction of the functional state of an athlete’s body under extreme loads. RF patent for invention. Patent RUS № RU 2022622848. 11.11.2022. Available at: https://istina.msu.ru/patents/510751941/ Accessed: 29.01.2024.

87. Pustovoit V. I., Balakin E. I., Khan A. V., Murtazin A. A., Maksjutov N. F., Merkulova P. S., Kubyshev K. A. The combination of traditional cardiorespiratory markers during treadmill testing "to failure" in athletes, depending on professional activity. Sports medicine: research and practice. 2022;12(3):51–59. (In Russ.) DOI: 10.47529/2223-2524.2022.3.5.