Prospects for protecting normal tissues during chemotherapy of malignant tumors

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Abstract

This article presents research data aimed at exploiting the advantages of normal cells integrated into the body’s system in chemotherapy for malignant tumors, compared to tumor cells that lose their connection with its regulatory systems during progression. Publications from the biomedical literature databases SciVerse Scopus, PubMed, Web of Science, and the Russian Science Citation Index were analyzed. Information from 70 publications, including in vitro and in vivo experimental data, as well as clinical studies, was used, 22 of which were published over the past five years. The possibility of harnessing the phagocytic activity of resident macrophages by supersaturating them with phagocytized particles containing an adsorbed protective agent, such as folic acid, which is an antidote to methotrexate is considered. As a result, resident macrophages of the hematopoietic organs and intestines create a long-term protective depot, allowing the use of high doses of methotrexate. In cases of using encapsulated forms of chemotherapeutic agents, which are taken up by macrophages and dramatically reduce their circulation time in the bloodstream, blocking their phagocytic capacity with similarly loaded particles is proposed. This will, on the one hand, increase the capsule circulation time in the bloodstream, and, on the other, allow for the combined action of the first drug with a second, for example, methotrexate. Since the activity of some important xenobiotic-metabolizing enzymatic systems, particularly cytochrome P450, is partially or completely lost by tumor cells during their dedifferentiation, the use of transport forms of protective agents that are activated by these enzymatic systems in normal cells and inaccessible to tumor cells is proposed. Another advantage of normal cells is that the action of low doses of cytostatics on checkpoints stops their proliferation, unlike tumor clone resistant to the cytostatic agent. These clones will continue to divide and become selectively susceptible to mitotic toxins. Thus, the use of multilevel mechanisms of protection of normal tissues in antitumor chemotherapy is relevant for increasing the safety and effectiveness of treatment.

About the authors

G. A. Belitsky

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Email: mgyakubovskaya@mail.ru
ORCID iD: 0000-0002-3167-7204
Russian Federation, 24 Kashirskoe Shosse, Moscow 115522

K. I. Kirsanov

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; RUDN University

Email: mgyakubovskaya@mail.ru
ORCID iD: 0000-0002-8599-6833
Russian Federation, 24 Kashirskoe Shosse, Moscow 115522; 6 Miklukho-Maklaya St., Moscow 117198

T. I. Fetisov

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Email: mgyakubovskaya@mail.ru
ORCID iD: 0000-0002-5082-9883
Russian Federation, 24 Kashirskoe Shosse, Moscow 115522

L. G. Solenova

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Email: mgyakubovskaya@mail.ru
ORCID iD: 0000-0002-4443-8376
Russian Federation, 24 Kashirskoe Shosse, Moscow 115522

Marianna G. Yakubovskaya

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Author for correspondence.
Email: mgyakubovskaya@mail.ru
ORCID iD: 0000-0002-9710-8178
Russian Federation, 24 Kashirskoe Shosse, Moscow 115522

References

  1. Tyulandin S.A. Targeted therapy: twenty years of successes and failures. Prakticheskaya
  2. Svet-Moldavsky G.Ya., Pavlotsky A.I., Ravkina L.I. The principle of selective protection in the chemotherapy of malignant tumors. Bulletin of the USSR Academy of Medical Sciences 1967,5:6. (In Russ.).
  3. Oosterom N., de Jonge R., Smith D.E.C. et al. Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia. PloS One 2019;14(9):e0221591. doi: 10.1371/journal.pone.0221591
  4. Skärby T.V., Anderson H., Heldrup J. et al. High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia 2006;20(11):1955–62. doi: 10.1038/sj.leu.2404404
  5. Olivo L.B., de Oliveira Henz P., Wermann S. et al. Anticipating leucovorin rescue therapy in patients with osteosarcoma through methotrexate population pharmacokinetic model. Pharmaceutics 2024;16(9):1180. doi: 10.3390/pharmaceutics16091180
  6. Latif M.F., Azam F., Hassan Tirmazy S.H., Bukhari N. Treatment outcomes of gestational trophoblastic disease, experience from Saudi Arabia. J Ayub Med Coll Abbottabad 2024;36(2):289–93. doi: 10.55519/jamc-02-12695
  7. Bates T.R., Blumenthal H.P., Pieniaszek H.J. Jr. Time course of free and N4-acetylated sulfapyridine concentrations in the plasma and saliva of man after sulfasalazine (salicylazosulfapyridine) administration: preliminary findings. Res Commun Chem Pathol Pharmacol 1976;15(1):183–9.
  8. A-Gonzalez N., Quintana J.A., García-Silva S. et al. Phagocytosis imprints heterogeneity in tissue-resident macrophages. J Exp Med 2016;214(5):1281–96. doi: 10.1084/jem.20161375
  9. Wang L., Hu Z., Zhang W. et al. Promoting macrophage phagocytosis of cancer cells for effective cancer immunotherapy. Biochem Pharmacol 2025;232:116712. doi: 10.1016/j.bcp.2024.116712
  10. Fu L.Q., Du W.L., Cai M.H. et al. The roles of tumor-associated macrophages in tumor angiogenesis and metastasis. Cell Immunol 2020;353:104119. doi: 10.1016/j.cellimm.2020.104119
  11. Cassetta L., Pollard J.W. A timeline of tumour-associated macrophage biology. Nature Review Cancer 2023;23(4):238–57. doi: 10.1038/s41568-022-00547-1
  12. Qin R., Ren W., Ya G. et al. Role of chemokines in the crosstalk between tumor and tumor-associated macrophages. Clin Exp Med 2023;23(5):1359–73. doi: 10.1007/s10238-022-00888-z
  13. Arora L., Kalia M., Pal D. Role of macrophages in cancer progression and targeted immunotherapies. Adv Protein Chem Struct Biol 2023;135:281–311. doi: 10.1016/bs.apcsb.2022.11.010
  14. Wang Y., Jiang H., Luo H. et al. An IL-4/21 inverted cytokine receptor improving CAR-T cell potency in immunosuppressive solid-tumor microenvironment. Front Immunol 2019;10:1691. doi: 10.3389/fimmu.2019.01691
  15. Zhang G., Gao Z., Guo X. et al. CAP2 promotes gastric cancer metastasis by mediating the interaction between tumor cells and tumor-associated macrophages. J Clin Invest 2023;133(21):e166224. doi: 10.1172/jci166224
  16. Dallavalasa S., Beeraka N.M., Basavaraju C.G. et al. The role of tumor associated macrophages (TAMs) in cancer progression, chemoresistance, angiogenesis and metastasis – current status. Curr Med Chem 2021;28(39):8203–36. doi: 10.2174/0929867328666210720143721
  17. Viola A., Munari F., Sánchez-Rodríguez R. et al. The metabolic signature of macrophage responses. Front Immunol 2019;10:1462. doi: 10.3389/fimmu.2019.01462
  18. Wang H., Wang X., Zhang X., Xu W. The promising role of tumor-associated macrophages in the treatment of cancer. Drug Resist Updat 2024;73:101041. doi: 10.1016/j.drup.2023.101041
  19. Mirkasymov A.B., Zelepukin I.V., Nikitin P.I. et al. In vivo blockade of mononuclear phagocyte system with solid nanoparticles: efficiency and affecting factors. J Control Release 2021;330:111–8. doi: 10.1016/j.jconrel.2020.12.004
  20. Mirkasymov A.B., Zelepukin I.V., Ivanov I.N. et al. Macrophage blockade using nature-inspired ferrihydrite for enhanced nanoparticle delivery to tumor. Int J Pharm 2022;621:121795. doi: 10.1016/j.ijpharm.2022.121795
  21. Zelepukin I.V., Shevchenko K.G., Deyev S.M. Rediscovery of mononuclear phagocyte system blockade for nanoparticle drug delivery. Dokl Biochem Biophys 2025;525(1):569–73. doi: 10.1038/s41467-024-48838-5
  22. Zelepukin I.V., Shipunova V.O., Mirkasymov A.B. et al. Synthesis and characterization of hybrid core-shell Fe3O4/SiO2 nanoparticles for biomedical applications. Acta Naturae 2017;9(4):58–65.
  23. Gordon S.R., Maute R.L., Dulken B.W. et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 2017;545(7655):495–9. doi: 10.1038/nature22396
  24. Li Q., Han J., Yang Y., Chen Y. PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy. Front Immunol 2022;13:1070961. doi: 10.3389/fimmu.2022.1070961
  25. Bomstein Y., Ophir R., Harshemes H., Ben-Efraim S. Release of immunosuppressive factor(s) by MOPC-315 murine plasmacytoma cells: a possible mechanism of defence. Anticancer Res 1993;13(6A):2125–9.
  26. Soldatos T.G., Dimitrakopoulou-Strauss A., Larribere L. et al. Retrospective side effect profiling of the metastatic melanoma combination therapy ipilimumab-nivolumab using adverse event data. Diagnostics (Basel) 2018;8(4):76. doi: 10.3390/diagnostics8040076
  27. Sabadie N., Richter-Reichhelm H.B., Saracci R. et al. Inter-individual differences in oxidative benzo(a)pyrene metabolism by normal and tumorous surgical lung specimens from 105 lung cancer patients. Int J Cancer 1981;27(4):417–25. doi: 10.1002/ijc.2910270402
  28. Patterson L.H., Murray G.I. Tumour cytochrome P450 and drug activation. Curr Pharm Des 2002;8(15):1335–47. doi: 10.2174/1381612023394502
  29. Leskelä S., Honrado E., Montero-Conde C. et al. Cytochrome P450 3A5 is highly expressed in normal prostate cells but absent in prostate cancer. Endocr Relat Cancer 2007;14(3):645–54. doi: 10.1677/erc-07-0078
  30. Nekvindova J., Mrkvicova A., Zubanova V. et al. Hepatocellular carcinoma: Gene expression profiling and regulation of xenobiotic-metabolizing cytochromes P450. Biochem Pharmacol 2020;177:113912. doi: 10.1016/j.bcp.2020.113912
  31. Oyama T., Sugio K., Isse T. et al. Expression of cytochrome P450 in non-small cell lung cancer. Front Biosci 2008 May 1;13:5787–93. doi: 10.2741/3116
  32. Işcan M., Ada A.O. Cytochrome P-450 polymorphisms and clinical outcome in patients with non-small cell lung cancer. Turk J Pharm Sci 2017;14(3):319–23. doi: 10.4274/tjps.28291
  33. Bulus H., Oguztuzun S., Güler Simsek G. et al. Expression of CYP and GST in human normal and colon tumor tissues. Biotech Histochem 2019;94(1):1–9. doi: 10.1080/10520295.2018.1493220
  34. Tornio A., Backman J.T. Cytochrome P450 in pharmacogenetics: an update. Adv Pharmacol 2018;83:3–32. doi: 10.1016/bs.apha.2018.04.007
  35. Raunio H., Rahnasto-Rilla M. CYP2A6: genetics, structure, regulation, and function. Drug Metabol Drug Interact 2012;27(2):73–88. doi: 10.1515/dmdi-2012-0001
  36. Zhao M., Ma J., Li M. et al. Cytochrome P450 enzymes and drug metabolism in humans. Int J Mol Sci 2021;22(23):12808. doi: 10.3390/ijms222312808
  37. El-Sherbeni A.A., El-Kadi A.O. Microsomal cytochrome P450 as a target for drug discovery and repurposing. Drug Metab Rev 2017;49(1):1–17. doi: 10.1080/03602532.2016.1257021
  38. Murayama N., Sai K., Nakajima Y. et al. Expression of CYP2A6 in tumor cells augments cellular sensitivity to tegafur. Jpn J Cancer Res 2001;92(5):524–8. doi: 10.1111/j.1349-7006.2001.tb01125.x
  39. Komatsu T., Yamazaki H., Shimada N. et al. Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos 2000;28(12):1457–63.
  40. Belitsky G.A., Bukhman V.M., Konopleva I.A. Changes in toxic and antitumor properties of ftorafur by induction or inhibition of the microsomal enzymes activity. Cancer Chemother Pharmacol 1981;6(2):183–7. doi: 10.1007/bf00262340
  41. Pastina I., Giovannetti E., Chioni A., Sissung T.M. et al. Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in castration-resistant prostate cancer (CRPC) patients. BMC Cancer 2010;10:511. doi: 10.1186/1471-2407-10-511
  42. Abdul Aziz A.A., Md Salleh M.S., Mohamad I. et al. Single-nucleotide polymorphisms and mRNA expression of CYP1B1 influence treatment response in triple negative breast cancer patients undergoing chemotherapy. J Genet 2018;97(5):1185–94.
  43. Mangó K., Fekete F., Kiss Á.F. et al. Association between CYP2B6 genetic variability and cyclophosphamide therapy in pediatric patients with neuroblastoma. Sci Rep 2023;13(1):11770. doi: 10.1038/s41598-023-38983-0
  44. Rao B., Lain S., Thompson A.M. p53-based cyclotherapy: exploiting the ‘guardian of the genome’ to protect normal cells from cytotoxic therapy. Br J Cancer 2013;109(12):2954–8. doi: 10.1038/bjc.2013.702
  45. Kranz D., Dobbelstein M. Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy. Cancer Res 2006;66(21):10274–80. doi: 10.1158/0008-5472.Can-06-1527
  46. Ye H., Qian L., Zhu S. et al. IL-1Ra protects hematopoietic cells from chemotoxicity through p53-induced quiescence. FASEB J 2019;33(11):12135–45. doi: 10.1096/fj.201900788RR
  47. Blagosklonny M.V., Bishop P.C., Robey R. et al. Loss of cell cycle control allows selective microtubule-active drug-induced Bcl-2 phosphorylation and cytotoxicity in autonomous cancer cells. Cancer Res 2000;60(13):3425–8.
  48. Mull B.B., Livingston J.A., Patel N. et al. Specific, reversible G1 arrest by UCN-01 in vivo provides cytostatic protection of normal cells against cytotoxic chemotherapy in breast cancer. Br J Cancer 2020;122(6):812–22. doi: 10.1038/s41416-019-0707-z
  49. Blagosklonny M.V. Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells. Oncotarget 2023;14:193–206. doi: 10.18632/oncotarget.28382
  50. George S., Kasimis B.S., Cogswell J. et al. Phase I study of flavopiridol in combination with Paclitaxel and Carboplatin in patients with non-small-cell lung cancer. Clin Lung Cancer 2008;9(3):160–5. doi: 10.3816/CLC.2008.n.024
  51. Blagosklonny M.V. Treatment with inhibitors of caspases, that are substrates of drug transporters, selectively permits chemotherapy-induced apoptosis in multidrug-resistant cells but protects normal cells. Leukemia 2001;15(6):936–41. doi: 10.1038/sj.leu.2402127
  52. Lai A.Y., Sorrentino J.A., Dragnev K.H. et al. CDK4/6 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in preclinical models and enhances T-cell activation in patients with SCLC receiving chemotherapy. J Immunother Cancer 2020;8(2):e000847. doi: 10.1136/jitc-2020-000847
  53. Huang Y., Ibrado A.M., Reed J.C. et al. Co-expression of several molecular mechanisms of multidrug resistance and their significance for paclitaxel cytotoxicity in human AML HL-60 cells. Leukemia 1997;11(2):253–7. doi: 10.1038/sj.leu.2400557
  54. Blagosklonny M.V., Robey R., Bates S., Fojo T. Pretreatment with DNA-damaging agents permits selective killing of checkpoint-deficient cells by microtubule-active drugs. J Clin Invest 2000; 105(4):533–9. doi: 10.1172/jci8625
  55. Choong M.L., Yang H., Lee M.A., Lane D.P. Specific activation of the p53 pathway by low dose actinomycin D: a new route to p53 based cyclotherapy. Cell Cycle 2009;8(17):2810–8. doi: 10.4161/cc.8.17.9503
  56. Zhang J., Xiang D., Zhu S. et al. Interleukin 1 receptor antagonist inhibits normal hematopoiesis and reduces lethality and bone marrow toxicity of 5-fluouracil in mouse. Biomed Pharmacother 2009;63(7):501–8. doi: 10.1016/j.biopha.2008.09.014
  57. Yu H., Wu M., Wen B. et al. Antagonist effect of Interleukin 1 receptor on normal thymopoiesis and thymus toxicity of 5-azacytidine in mouse. Am J Transl Res 2016;8(2):1237–45.
  58. Chen X., Lowe M., Herliczek T. et al. Protection of normal proliferating cells against chemotherapy by staurosporine-mediated, selective, and reversible G(1) arrest. J Natl Cancer Inst 2000;92(24):1999–2008. doi: 10.1093/jnci/92.24.1999
  59. Chen X., Lowe M., Keyomarsi K. UCN-01-mediated G1 arrest in normal but not tumor breast cells is pRb-dependent and p53-independent. Oncogene 1999;18(41):5691–702. doi: 10.1038/sj.onc.1202948
  60. Jackson R.C., Di Veroli G.Y., Koh S.B. et al. Modelling of the cancer cell cycle as a tool for rational drug development: A systems pharmacology approach to cyclotherapy. PLoS Comput Biol 2017;13(5):e1005529. doi: 10.1371/journal.pcbi.1005529
  61. Laskin J.J., Sandler A.B. Epidermal growth factor receptor: a promising target in solid tumours. Cancer Treat Rev 2004;30(1):1–17. doi: 10.1016/j.ctrv.2003.10.002
  62. Dickerson H., Diab A., Al Musaimi O. Epidermal growth factor receptor tyrosine kinase inhibitors in cancer: current use and future prospects. Int J Mol Sci 2024;25(18):10008. doi: 10.3390/ijms251810008
  63. Zhang Y.G., Du Q., Fang W.G. et al. Tyrphostin AG1478 suppresses proliferation and invasion of human breast cancer cells. Int J Oncol 2008;33(3):595–602.
  64. Saleh K., Al Sakhen M., Kanaan S. et al. Antitumor activity of the new tyrphostin briva against BRAF(V600E)-mutant colorectal carcinoma cells. Invest New Drugs 2023;41(6):791–801. doi: 10.1007/s10637-023-01402-2
  65. Smith W.W. Protective effect of a colchicine derivative in mice exposed to x-radiation. Science 1958;127(3294):340–1. doi: 10.1126/science.127.3294.340
  66. Hussein M., Maglakelidze M., Richards D.A. et al. Myeloprotective effects of trilaciclib among patients with small cell lung cancer at increased risk of chemotherapy-induced myelosuppression: pooled results from three phase 2, randomized, double-blind, placebo-controlled studies. Cancer Manag Res 2021;13:6207–18. doi: 10.2147/cmar.S313045
  67. Tan A.R., Wright G.S., Thummala A.R. et al. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol 2019;20(11):1587–601. doi: 10.1016/s1470-2045(19)30616-3
  68. Johnson S.M., Torrice C.D., Bell J.F. et al. Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. J Clin Invest 2010;120(7):2528–36. doi: 10.1172/jci41402
  69. Wei L., Leibowitz B.J., Wang X. et al. Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice. J Clin Invest 2016;126(11):4076–87. doi: 10.1172/jci88410
  70. Glaviano A., Wander S.A., Baird R.D. et al. Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment. Drug Resist Updat 2024;76:101103. doi: 10.1016/j.drup.2024.101103

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