SpringerLink
Log in

Characteristics of the Antitumor Effect of Doxorubicin and Pegylated Hyaluronidase on Models of Rat Brain Tumors

  • Published:
Bulletin of Experimental Biology and Medicine Aims and scope

Hyaluronidase increases tissue permeability and diffusion of the extracellular fluid by cleaving hyaluronan, the primary component of the extracellular matrix. Hyaluronidase pegylation (Hyal-PEG) decreases its clearance and enhances biodistribution. The pro- and anticancer activity of Hyal-PEG and a combination of Hyal-PEG with doxorubicin were studied in vitro (morphological analysis of rat glioblastoma 101.8 spheroids) and in vivo (by the survival time of rats after intracerebral transplantation of the tumor and morphological analysis). In the presence of doxorubicin and Hyal-PEG in the culture medium in vitro, spheroids lost their ability to adhere to the substrate and disintegrate into individual cells. Intracerebral transplantation of the tumor tissue with Hyal-PEG did not accelerate glioblastoma growth. The mean survival time for animals receiving transplantation of the tumor alone and in combination with Hyal-PEG was 13 and 20 days, respectively. In one rat with transplanted tumor and Hyal-PEG, this parameter increased by 53%. The survival time of rats receiving systemic therapy with doxorubicin and Hyal-PEG significantly increased (p=0.003). Antitumor effect of therapeutic doses of doxorubicin combined with Hyal-PEG was demonstrated on the model of rat glioblastoma 101.8 in vitro. Hyal-PEG inhibited adhesion of tumor cells, but did not cause their death. Transplantation of Hyal-PEG-treated tumor did not reduce animal survival time. Systemic administration of therapeutic doses of doxorubicin with Hyal-PEG increased survival time of rats with glioblastoma 101.8.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Infante JR, Korn RL, Rosen LS, LoRusso P, Dychter SS, Zhu J, Maneval DC, Jiang P, Shepard HM, Frost G, Von Hoff DD, Borad MJ, Ramanathan RK. Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours. Br. J. Cancer. 2018;118(2):153-161. https://doi.org/10.1038/bjc.2017.327

    Article  CAS  PubMed  Google Scholar 

  2. Michalczyk M, Humeniuk E, Adamczuk G, Korga-Plewko A. Hyaluronic acid as a modern approach in anticancer therapy-review. Int. J. Mol. Sci. 2022;24(1):103. https://doi.org/10.3390/ijms24010103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pibuel MA, Poodts D, Díaz M, Hajos SE, Lompardía SL. The scrambled story between hyaluronan and glioblastoma. J. Biol. Chem. 2021;296:100549. https://doi.org/10.1016/j.jbc.2021.100549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Matcovschii V, Lisii D, Gudumac V, Dorosenco S. Selective interstitial doxorubicin for recurrent glioblastoma. Clin. Case Rep. 2019;7(12):2520-2525. https://doi.org/10.1002/ccr3.2546

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jadin L, Pastorino S, Symons R, Nomura N, Jiang P, Juarez T, Makale M, Kesari S. Hyaluronan expression in primary and secondary brain tumors. Ann. Transl. Med. 2015;3(6):80. https://doi.org/10.3978/j.issn.2305-5839.2015.04.07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kai F, Drain AP, Weaver VM. The extracellular matrix modulates the metastatic journey. Dev. Cell. 2019;49(3):332-346. https://doi.org/10.1016/j.devcel.2019.03.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu W, Nestorovich EM. Probing protein nanopores with poly(ethylene glycol)s. Proteomics. 2022;22(5-6):e2100055. https://doi.org/10.1002/pmic.202100055

    Article  CAS  PubMed  Google Scholar 

  8. Ward C, Meehan J, Gray ME, Murray AF, Argyle DJ, Kunkler IH, Langdon SP. The impact of tumour pH on cancer progression: strategies for clinical intervention. Explor. Target. Antitumor Ther. 2020;1(2):71-100. https://doi.org/10.37349/etat.2020.00005

  9. Chao KL, Muthukumar L, Herzberg O. Structure of human hyaluronidase-1, a hyaluronan hydrolyzing enzyme involved in tumor growth and angiogenesis. Biochemistry. 2007;46(23):6911-6920. https://doi.org/10.1021/bi700382g

    Article  CAS  PubMed  Google Scholar 

  10. Anchordoquy TJ, Simberg D. Watching the gorilla and questioning delivery dogma. J. Control. Release. 2017;262: 87-90. https://doi.org/10.1016/j.jconrel.2017.07.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Campello E, Ilich A, Simioni P, Key NS. The relationship between pancreatic cancer and hypercoagulability: a comprehensive review on epidemiological and biological issues. Br J Cancer. 2019;121(5):359-371. https://doi.org/10.1038/s41416-019-0510-x

    Article  PubMed  PubMed Central  Google Scholar 

  12. Thakur M, Evans B, Schindewolf M, Baumgartner I, Döring Y. Neutrophil extracellular traps affecting cardiovascular health in infectious and inflammatory diseases. Cells. 2021;10(7):1689. https://doi.org/10.3390/cells10071689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Petrey AC, Obery DR, Kessler SP, Zawerton A, Flamion B, de la Motte CA. Platelet hyaluronidase-2 regulates the early stages of inflammatory disease in colitis. Blood. 2019;134(9):765-775. https://doi.org/10.1182/blood.2018893594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Arutyunyan IV, Soboleva AG, Kovtunov EA, Kosyreva AM, Kudelkina VV, Alekseeva AI, Elchaninov AV, Jumaniyazova ED, Goldshtein DV, Bolshakova GB, Fatkhudinov TKh. Gene expression profile of 3D spheroids in comparison with 2D cell cultures and tissue strains of diffuse high-grade gliomas. Bull. Exp. Biol. Med. 2023;175(4):576-584. https://doi.org/10.1007/s10517-023-05906-y

    Article  CAS  PubMed  Google Scholar 

  15. Fedoseeva VV, Khalansky AS, Mkhitarov VA, Tsvetkov IS, Malinovskaya YA, Maksimenko OO, Gelperina SE, Balabanyan VY, Razzhivina VA, Gorelikov PL, Mikhailova LP, Makarova OV. Anti-tumor activity of doxorubicin-loaded poly(lactide-co-glycolide) nanoparticles in the experimental glioblastoma. Klin. Eksper. Morfol. 2017;(2):65-71. Russian.

  16. Uvarkina TP, Kakhoyan EG. Patent RU No. 2608492. Hyaluronidase and method of its application. Bull. No. 1. Published January 18, 2017.

  17. Dygai AM, Zyuzkov GN, Zhdanov VV, Udut EV, Artamonov AV, Bekarev AA, Madonov PG, Kinsht DN, Miroshnichenko LA, Khrichkova TYu, Simanina EV, Stavrova LA, Chaikovskiy AV, Markova TS, Minakova MYu, Gurto RV. Mechanisms for hepatoprotective effects of hyaluronidase immobilized by the nanotechnology method of electron-beam synthesis. Bull. Exp. Biol. Med. 2011;151(1):74-78. https://doi.org/10.1007/s10517-011-1263-6

  18. Manual for Preclinical Studies of New Pharmacological Substances. Part II, Mironov AN, ed. Moscow, 2012. P. 640-654. Russian.

  19. Whatcott CJ, Han H, Posner RG, Hostetter G, Von Hoff DD. Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look. Cancer Discov. 2011;1(4):291-296. https://doi.org/10.1158/2159-8290.CD-11-0136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bouga H, Tsouros I, Bounias D, Kyriakopoulou D, Stavropoulos MS, Papageorgakopoulou N, Theocharis DA, Vynios DH. Involvement of hyaluronidases in colorectal cancer. BMC Cancer. 2010;10:499. https://doi.org/10.1186/1471-2407-10-499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cheng XB, Sato N, Kohi S, Yamaguchi K. Prognostic impact of hyaluronan and its regulators in pancreatic ductal adenocarcinoma. PLoS One. 2013;8(11):e80765. https://doi.org/10.1371/journal.pone.0080765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chanmee T, Ontong P, Itano N. Hyaluronan: A modulator of the tumor microenvironment. Cancer Lett. 2016;375(1):20-30. https://doi.org/10.1016/j.canlet.2016.02.031

    Article  CAS  PubMed  Google Scholar 

  23. Berdiaki A, Neagu M, Spyridaki I, Kuskov A, Perez S, Nikitovic D. Hyaluronan and reactive oxygen species signaling-novel cues from the matrix? Antioxidants (Basel). 2023;12(4):824. https://doi.org/10.3390/antiox12040824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dzhalilova DS, Zolotova NA, Mkhitarov VA, Kosyreva AM, Tsvetkov IS, Khalansky AS, Alekseeva AI, Fatkhudinov TH, Makarova OV. Morphological and molecular-biological features of glioblastoma progression in tolerant and susceptible to hypoxia Wistar rats. Sci. Rep. 2023;13(1):12694. https://doi.org/10.1038/s41598-023-39914-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Campanella R, Guarnaccia L, Cordiglieri C, Trombetta E, Caroli M, Carrabba G, La Verde N, Rampini P, Gaudino C, Costa A, Luzzi S, Mantovani G, Locatelli M, Riboni L, Navone SE, Marfia G. Tumor-educated platelets and angiogenesis in glioblastoma: another brick in the wall for novel prognostic and targetable biomarkers, changing the vision from a localized tumor to a systemic pathology. Cells. 2020;9(2):294. https://doi.org/10.3390/cells9020294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Balykova LA, Inchina VI, Tarasova TV, Mosina LM, Gvozdikova EN, Khaydar DA, Myandina GI, Ryzhakin SM, Saushev IV. The effectiveness of liposomal doxorubicin hydrochloride in combination with cyclophosphan in the treatment of breast cancer in an experiment. Research’n Pract. Med. J. 2021;8(4):23-32. Russian. https://doi.org/10.17709/2410-1893-2021-8-4-2

  27. Struve J, Maher PC, Li YQ, Kinney S, Fehlings MG, Kuntz C 4th, Sherman LS. Disruption of the hyaluronan-based extracellular matrix in spinal cord promotes astrocyte proliferation. Glia. 2005;52(1):16-24. https://doi.org/10.1002/glia.20215

    Article  PubMed  Google Scholar 

  28. Guo J, Zhu Y, Yu L, Li Y, Guo J, Cai J, Liu L, Wang Z. Aspirin inhibits tumor progression and enhances cisplatin sensitivity in epithelial ovarian cancer. PeerJ. 2021;9:e11591. https://doi.org/10.7717/peerj.11591

    Article  PubMed  PubMed Central  Google Scholar 

  29. Jiang D, Liang J, Noble PW. Hyaluronan as an immune regulator in human diseases. Physiol. Rev. 2011;91(1):221-264. https://doi.org/10.1152/physrev.00052.2009

    Article  CAS  PubMed  Google Scholar 

  30. Grecian R, Whyte MKB, Walmsley SR. The role of neutrophils in cancer. Br. Med. Bull. 2018;128(1):5-14. https://doi.org/10.1093/bmb/ldy029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Worst T, Erben P. CDKN2A as transcriptomic marker for muscle-invasive bladder cancer risk stratification and therapy decision-making. Sci. Rep. 2018;8(1):14383. https://doi.org/10.1038/s41598-018-32569-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ouhtit A, Rizeq B, Saleh HA, Rahman MM, Zayed H. Novel CD44-downstream signaling pathways mediating breast tumor invasion. Int. J. Biol. Sci. 2018;14(13):1782-1790. https://doi.org/10.7150/ijbs.23586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, Moscow, Russia

    V. V. Kudelkina, A. M. Kosyreva, A. I. Alekseeva, E. A. Miroshnichenko & I. V. Arutyunyan

  2. Novosibirsk State Medical University, Ministry of Health of the Russian Federation, Novosibirsk, Russia

    Ts. Magsarzhav, A. P. Nadeev & P. G. Madonov

Authors
  1. V. V. Kudelkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ts. Magsarzhav
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. M. Kosyreva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. P. Nadeev
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. G. Madonov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. I. Alekseeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. A. Miroshnichenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. I. V. Arutyunyan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V. V. Kudelkina.

Additional information

Translated from Kletochnye Tekhnologii v Biologii i Meditsine, No. 1, pp. 37-44, March, 2024

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kudelkina, V.V., Magsarzhav, T., Kosyreva, A.M. et al. Characteristics of the Antitumor Effect of Doxorubicin and Pegylated Hyaluronidase on Models of Rat Brain Tumors. Bull Exp Biol Med (2024). https://doi.org/10.1007/s10517-024-06147-3

Download citation

  • Received:

  • Published:

  • DOI: https://doi.org/10.1007/s10517-024-06147-3

Key Words

Search

Navigation