Significance of interleukins and chemokines in development of vincristine polyneuropathy in children with acute lymphoblastic leukemia

Cover Page

Cite item

Full Text

Abstract

Objective. To analyze the content of interleukins, chemokines in plasma and liquor of children with acute lymphoblastic leukemia depending on the development of vincristine polyneuropathy.

Materials and methods. A single-center prospective cohort non-randomized study was conducted involving 131 children aged 3 to 17 years with acute lymphoblastic leukemia who received chemotherapy according to the protocol. The content of interleukins and chemokines in blood plasma and liquor was assessed with the subsequent comparative analysis of the indicators in two groups depending on the development of vincristine polyneuropathy. The level of the studied parameters was determined before the administration of chemotherapy and on the 36th day of treatment using multiparametric immunofluorescence analysis.

Results. In the studied cohort of patients vincristine polyneuropathy was registered in 80.9 % (n = 106) of patients. In the majority of cases – 84.9 % (n = 90) neurotoxic complication developed during the induction stage of chemotherapy. In the clinical picture there dominated sensory and motor disorders in 70.7 % (n = 75) of patients. The data of electrophysiologic study testified to motor axonal polyneuropathy with peroneal nerves lesion. When comparing the primary level of interleukins with their concentration after completion of the induction stage of chemotherapy, it was found that in children without vincristine polyneuropathy there was a statistically significant increase in almost all proinflammatory and anti-inflammatory interleukins. Besides, in this group high and medium direct statistically significant correlations between these cytokines were established. Especially close correlations were noted between pro-inflammatory IL-1, IL-17 and anti-inflammatory interleukins (IL-10, IL-13, IL-22 and IL-27). Additionally, in patients with vincristine polyneuropathy, a 3.7-fold increase in CXCL10 (IP-10) and a 1.4-fold increase in CXCL12 (SDF-1α) chemokines (p = 0.005 and p = 0.054, respectively) was detected in the liquor during the completion of the induction phase of chemotherapy.

Conclusions. The balanced interleukin response in children with acute lymphoblastic leukemia receiving vincristine probably reflects a link between the immune and nervous systems aimed at preventing peripheral nerve damage. An imbalance of proinflammatory and anti-inflammatory interleukins may contribute to the development of vincristine polyneuropathy. Significant increase in the content of chemokines CXCL10 (IP-10) and CXCL12 (SDF-1α) in the liquor of children with vincristine polyneuropathy gives grounds to consider them as biological markers of vincristine neurotoxicity.

About the authors

O. P. Kovtun

Ural State Medical University

Email: usma@usma.ru
ORCID iD: 0000-0002-5250-7351
SPIN-code: 9919-9048

MD, PhD, Professor, Academician of the Russian Academy of Sciences, Rector

Russian Federation, Yekaterinburg

O. V. Koryakina

Ural State Medical University; Regional Children’s Clinical Hospital

Author for correspondence.
Email: koryakina09@mail.ru
ORCID iD: 0000-0002-4595-1024
SPIN-code: 4880-6913

Candidate of Medical Sciences, Associate Professor, Department of Nervous Diseases, Neurosurgery and Medical Genetics

Russian Federation, Yekaterinburg; Yekaterinburg

V. V. Bazarnyi

Ural State Medical University

Email: vlad-bazarny@yandex.ru
ORCID iD: 0000-0003-0966-9571
SPIN-code: 4813-8710

MD, PhD, Professor, Chief Researcher of the Central Research Laboratory

Russian Federation, Yekaterinburg

A. V. Rezaykin

Ural State Medical University

Email: alexrez@yandex.ru
ORCID iD: 0000-0002-8665-5299
SPIN-code: 9225-0209

Candidate of Medical Sciences, Associate Professor, Department of Medical Physics and Digital Technologies

Russian Federation, Yekaterinburg

References

  1. Demidowicz E., Pogorzała M., Łęcka M., Żołnowska H., Marjańska A., Kubicka M., Kuryło-Rafińska B., Czyżewski K., Dębski R., Kołtan A., Richert-Przygońska M., Styczyński J. Outcome of Pediatric Acute Lymphoblastic Leukemia: Sixty Years of Progress. Anticancer Res. 2019; 39 (9): 5203–5207. doi: 10.21873/anticanres.13717.
  2. Cook J., Litzow M. Advances in Supportive Care for Acute Lymphoblastic Leukemia. Curr Hematol Malig Rep. 2020; 15 (4): 276–293. doi: 10.1007/s11899-020-00585-2.
  3. Zaeva G.E., Valiev T.T., Gavrilenko T.F. i dr. Otdalennye posledstviya terapii zlokachestvennykh opukholey u detey: 35-letniy opyt klinicheskikh nablyudeniy. Sovremennaya onkologiya 2015; 18 (1): 55–60 (in Russian).
  4. Inaba H., Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica 2020; 105 (11): 2524–2539. doi: 10.3324/haematol.2020.247031.
  5. Triarico S., Romano A., Attinà G., Capozza M.A., Maurizi P., Mastrangelo S., Ruggiero A. Vincristine-Induced Peripheral Neurop-athy (VIPN) in Pediatric Tumors: Mechanisms, Risk Factors, Strategies of Prevention and Treatment. Int J Mol Sci. 2021; 22 (8): 4112. doi: 10.3390/ijms22084112.
  6. Zhou L., Ao L., Yan Y., Li W., Ye A., Hu Y., Fang W., Li Y. The Therapeutic Potential of Chemokines in the Treatment of Chemotherapy-Induced Peripheral Neuropathy. Curr Drug Targets. 2020; 21 (3): 288–301. DOI: 10.2174/
  8. Qin B., Li Y., Liu X., Gong D., Zheng W. Notch activation enhances microglial CX3CR1/P38 MAPK pathway in rats model of vincristine-induced peripheral neuropathy. Neurosci Lett. 2020; 715: 134624. doi: 10.1016/j.neulet.
  9. 134624.
  10. Starobova H., Monteleone M., Adolphe C. et al. Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release. The Journal of experimental medicine 2021; 218 (5): e20201452. doi: 10.1084/jem.20201452.
  11. Wang X.M., Lehky T.J., Brell J.M., Dorsey S.G. Discovering cytokines as targets for chemotherapy-induced painful peripheral neuropathy. Cytokine 2012; 59 (1): 3–9. doi: 10.1016/j.cyto.2012.03.027.
  12. Singh G., Singh A., Singh P., Bhatti R. Bergapten Ameliorates Vincristine-Induced Peripheral Neuropathy by Inhibi-tion of Inflammatory Cytokines and NFκB Signaling. ACS Chem Neurosci. 2019; 10 (6): 3008–3017. doi: 10.1021/acschemneuro.9b00206.
  13. Gautam M., Ramanathan M. Saponins of Tribulus terrestris attenuated neuropathic pain induced with vincristine through central and peripheral mechanism. Inflam-mopharmacology 2019; 27 (4): 761–772. doi: 10.1007/s10787-018-0502-0.
  14. Lees J.G., Makker P.G.S., Tonkin R.S. et al. Immune-mediated processes implicated in chemotherapy-induced peripheral neuropathy. European journal of cancer 2017; 73: 22–29. doi: 10.1016/j.ejca.2016.12.006.
  15. Xu T., Zhang X.L., Ou-Yang H.D., Li Z.Y., Liu C.C., Huang Z.Z., Xu J., Wei J.Y., Nie B.L., Ma C. et al. Epigenetic upregula-tion of CXCL12 expression mediates antitubulin chemotherapeutics-induced neuropathic pain. Pain. 2017; 158: 637–648. doi: 10.1097/j.pain.0000000000000805.
  16. Old E.A., Nadkarni S., Grist J., Gentry C., Bevan S., Kim K.W., Mogg A.J., Perretti M., Malcangio M. Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain. J Clin Invest. 2014; 124 (5): 2023–36. doi: 10.1172/JCI71389.
  17. Fouda W., Aboyoussef A., Messiha B., Salman M., Taye A. New insights into the cytoprotective mechanism of nano curcumin on neuronal damage in a vincristine-induced neuropathic pain rat model. Pak J Pharm Sci. 2023; 36 (1): 149–157.
  18. Ostryy limfoblastnyy leykoz: klinicheskie rekomendatsii. Moscow: Ministerstvo zdravookhraneniya Rossiyskoy Federatsii, available at: https://cr.minzdrav.gov.ru/recomend/529_1 (in Russian).
  19. Common Terminology Criteria for Adverse Events (STSAE) Version 5.0. November 27, 2017, available at: https://ctep.cancer.go/protocolDevelopment/electronic_applications/ctc.htm.
  20. Sanadze A.G., Kasatkina L.F. Klinicheskaya elektromiografiya dlya prakticheskikh nevrologov. Moscow: Geotar-Media 2022; 80 (in Russian).
  21. Tay N., Laakso EL., Schweitzer D., Endersby R., Vetter I., Starobova H. Chemotherapy-induced peripheral neuropathy in children and adolescent cancer patients. Front Mol Biosci. 2022; 9: 1015746. doi: 10.3389/fmolb.2022.1015746.
  22. Kashtal'yan O.A., Ushakova L.Yu. Tsitokiny kak universal'naya sistema regulyatsii. Meditsinskie novosti 2017; 9: 3–7 (in Rus-sian).
  23. Fumagalli G., Monza L., Cavaletti G., Rigolio R., Meregalli C. Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy. Front Immunol. 2021; 11: 626687. doi: 10.3389/fimmu.2020.626687.
  24. Akhter N., Wilson A., Thomas R., Al-Rashed F., Kochumon S., Al-Roub A., Arefanian H., Al-Madhoun A., Al-Mulla F., Ahmad R., Sindhu S. ROS/TNF-α Crosstalk Triggers the Expression of IL-8 and MCP-1 in Human Monocytic THP-1 Cells via the NF-κB and ERK1/2 Mediated Signaling. Int J Mol Sci. 2021; 22 (19): 10519. doi: 10.3390/ijms221910519.
  25. Michlmayr D., McKimmie C. Role of CXCL10 in central nervous system inflammation. Int J Interferon Cytokine Mediator Res. 2014; 6: 1–18.
  26. Bhangoo S., Ren D., Miller R.J., Henry K.J., Lineswala J., Hamdouchi C., Li B., Mo-nahan P.E., Chan D.M., Ripsch M.S., White F.A. Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors. Mol Pain. 2007; 3: 38. doi: 10.1186/1744-8069-3-38.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Comparative analysis of CXCL10 (IP-10) and CXCL12 (SDF-1α) chemokines in the liquor of children with OLL depending on the development of EP at the stage of completion of induction chemotherapy

Download (74KB)
Indexing metadata

Copyright (c) 2023 Eco-Vector


 


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies