Oxaliplatin-induced haematological toxicity and splenomegaly in mice

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Abstract

Purpose

Haematological toxicities occur in patients receiving oxaliplatin. Mild anaemia (grade 1–2) is a common side effect and approximately 90% of recipients develop measurable spleen enlargement. Although generally asymptomatic, oxaliplatin-induced splenomegaly is independently associated with complications following liver resection for colorectal liver metastasis and separately with poorer patient outcomes. Here, we investigated oxaliplatin-induced haematological toxicities and splenomegaly in mice treated with escalating dosages comparable to those prescribed to colorectal cancer patients.

Methods

Blood was analysed, and smears assessed using Wright-Giemsa staining. Paw coloration was quantified as a marker of anaemia. Spleen weight and morphology were assessed for abnormalities relating to splenomegaly and a flow cytometry and multiplex cytokine array assessment was performed on splenocytes. The liver was assessed for sinusoidal obstructive syndrome.

Results

Blood analysis showed dose dependent decreases in white and red blood cell counts, and significant changes in haematological indices. Front and hind paws exhibited dose dependent and dramatic discoloration indicative of anaemia. Spleen weight was significantly increased indicating splenomegaly, and red pulp tissue exhibited substantial dysplasia. Cytokines and chemokines within the spleen were significantly affected with temporal upregulation of IL-6, IL-1α and G-CSF and downregulation of IL-1β, IL-12p40, MIP-1β, IL-2 and RANTES. Flow cytometric analysis demonstrated alterations in splenocyte populations, including a significant reduction in CD45+ cells. Histological staining of the liver showed no evidence of sinusoidal obstructive syndrome but there were signs suggestive of extramedullary haematopoiesis.

Conclusion

Chronic oxaliplatin treatment dose dependently induced haematological toxicity and splenomegaly characterised by numerous physiological and morphological changes, which occurred independently of sinusoidal obstructive syndrome.

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Most cited references 36

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Interleukin 1α and the inflammatory process.

Nelson C. Di Paolo, Dmitry Shayakhmetov (2016)

Inflammation occurs after disruption of tissue homeostasis by cell stress, injury or infection and ultimately involves the recruitment and retention of cells of hematopoietic origin, which arrive at the affected sites to resolve damage and initiate repair. Interleukin 1α (IL-1α) and IL-1β are equally potent inflammatory cytokines that activate the inflammatory process, and their deregulated signaling causes devastating diseases manifested by severe acute or chronic inflammation. Although much attention has been given to understanding the biogenesis of IL-1β, the biogenesis of IL-1α and its distinctive role in the inflammatory process remain poorly defined. In this review we examine key aspects of IL-1α biology and regulation and discuss its emerging importance in the initiation and maintenance of inflammation that underlie the pathology of many human diseases.

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Oxaliplatin-induced neuropathy: oxidative stress as pathological mechanism. Protective effect of silibinin.

Lorenzo Di Cesare Mannelli, Matteo Zanardelli, Paola Failli … (2012)

Oxaliplatin is the standard treatment for advanced colorectal cancer. Its dose-limiting toxicity is the development of a painful neuropathic syndrome sustained by unclear mechanisms. Although the oxidative hypothesis is a matter of debate, direct data about oxidative damage induced in vivo by anticancer agents are lacking and the efficacy of the available antioxidant compounds are unsatisfactory. In a rat model of painful oxaliplatin-induced neuropathy (2.4 mgkg(-1) i.p., daily for 21 days), we described an important component of oxidative stress. In the plasma of oxaliplatin-treated rats, the increases in carbonylated protein and thiobarbituric acid reactive substances were the index of the resultant protein oxidation and lipoperoxidation, respectively. The same pattern of oxidation was revealed also in the sciatic nerve, and in the spinal cord where the damage reached the DNA level. The antioxidant compound silibinin (100 mgkg(-1) per os), administered once a day, starting from the first day of oxaliplatin injection until the 20th, prevented oxidative damage as did α-tocopherol. Repetitive administration of silibinin, as well as α-tocopherol, reduced oxaliplatin-dependent pain induced by mechanical and thermal stimuli. Antioxidants were also able to improve motor coordination. The antineuropathic effect of both molecules improved by about 50% oxaliplatin-induced behavioral alterations. This study characterizes oxidative stress parameters in a rat model of oxaliplatin-induced neuropathy. A relationship between the improvement of oxidative alterations and pain relief is established in rats treated with natural antioxidant compounds like α-tocopherol and silibinin. Silibinin could be a valid therapeutic option for chemotherapy-induced neuropathy. Copyright Â© 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.

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Extramedullary hematopoiesis: a new look at the underlying stem cell niche, theories of development, and occurrence in animals.

Edward J. Johns, John M Christopher (2012)

Extramedullary hematopoiesis (EMH) is the formation and development of blood cells outside the medullary spaces of the bone marrow. Although widely considered an epiphenomenon, secondary to underlying primary disease and lacking serious clinical or diagnostic implications, the presence of EMH is far from incidental on a molecular basis; rather, it reflects a well-choreographed suite of changes involving stem cells and their microenvironment (the stem cell niche). The goals of this review are to reconsider the molecular basis of EMH based on current knowledge of stem cell niches and to examine its role in the pathophysiologic mechanisms of EMH in animals. The ability of blood cells to home, proliferate, and mature in extramedullary tissues of adult animals reflects embryonic patterns of hematopoiesis and establishment or reactivation of a stem cell niche. This involves pathophysiologic alterations in hematopoietic stem cells, extracellular matrix, stromal cells, and local and systemic chemokines. Four major theories involving changes in stem cells and/or their microenvironment can explain the development of most occurrences of EMH: (1) severe bone marrow failure; (2) myelostimulation; (3) tissue inflammation, injury, and repair; and (4) abnormal chemokine production. EMH has also been reported within many types of neoplasms. Understanding the concepts and factors involved in stem cell niches enhances our understanding of the occurrence of EMH in animals and its relationship to underlying disease. In turn, a better understanding of the prevalence and distribution of EMH in animals and its molecular basis could further inform our understanding of the hematopoietic stem cell niche.

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Author and article information

Contributors

Justin G. Lees:

ORCID: http://orcid.org/0000-0002-0874-2856

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing

Daniel White:

ORCID: http://orcid.org/0000-0001-6614-4793

Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing

Brooke A. Keating: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing

Mallory E. Barkl-Luke: Role: InvestigationRole: MethodologyRole: Writing – review & editing

Preet G. S. Makker: Role: InvestigationRole: MethodologyRole: Writing – review & editing

David Goldstein: Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing

Gila Moalem-Taylor:

ORCID: http://orcid.org/0000-0003-3828-9527

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing

Senthilnathan Palaniyandi: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 2 September 2020

Publication date Collection: 2020

Volume: 15

Issue: 9

Electronic Location Identifier: e0238164

Affiliations

[1 ] School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia

[2 ] Prince of Wales Clinical School, The University of New South Wales, Sydney, New South Wales, Australia

University of Kentucky, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: gila@ 123456unsw.edu.au (GM-T); justin.lees@ 123456unsw.edu.au (JGL)

Author information

Justin G. Lees http://orcid.org/0000-0002-0874-2856

Daniel White http://orcid.org/0000-0001-6614-4793

Gila Moalem-Taylor http://orcid.org/0000-0003-3828-9527

Article

Publisher ID: PONE-D-20-01939

DOI: 10.1371/journal.pone.0238164

PMC ID: 7467301

PubMed ID: 32877416

SO-VID: 152cbc90-6926-4bb1-ad08-047ab7e67300

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 21 January 2020

Date accepted : 11 August 2020

Page count

Figures: 6, Tables: 0, Pages: 18

Funding

Funded by: funder-id http://dx.doi.org/10.13039/501100001171, Cancer Institute NSW;

Award ID: 14/TPG/1-05

Award Recipient : David Goldstein

D.G. - Cancer Institute NSW Translational Program Grant – “Chemotherapy-induced Peripheral Neuropathy: Assessment strategies, Treatment and Risk Factors” (ID # 14/TPG/1-05; http://www.cancerinstitute.org.au). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability All relevant data are available in figshare: Fig.1 A-F.xlsx https://doi.org/10.6084/m9.figshare.12831758 Fig.2 A-B.xlsx https://doi.org/10.6084/m9.figshare.12831782 Fig.3 A-G.xlsx https://doi.org/10.6084/m9.figshare.12831791 Fig.4 A-H.xlsx https://doi.org/10.6084/m9.figshare.12831794 Fig.5 A-H.xlsx https://doi.org/10.6084/m9.figshare.12831803.

Oxaliplatin-induced haematological toxicity and splenomegaly in mice

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Most cited references 36

Interleukin 1α and the inflammatory process.

Oxaliplatin-induced neuropathy: oxidative stress as pathological mechanism. Protective effect of silibinin.

Extramedullary hematopoiesis: a new look at the underlying stem cell niche, theories of development, and occurrence in animals.

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