Oxaliplatin-induced haematological toxicity and splenomegaly in mice.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Hematologic Tests*; Oxaliplatin/*adverse effects ; Splenomegaly/*chemically induced; Animals ; Cytokines/metabolism ; Dose-Response Relationship, Drug ; Liver/drug effects ; Liver/pathology ; Male ; Mice ; Organ Size/drug effects ; Phenotype ; Spleen/drug effects ; Spleen/pathology ; Splenomegaly/metabolism ; Splenomegaly/pathology ; Time Factors

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

Muscle Nerve. 2018 Apr;57(4):650-658. (PMID: 28881481)
Toxicol Appl Pharmacol. 1981 Sep 30;60(3):398-409. (PMID: 7292478)
Colorectal Dis. 2019 Jan;21(1):100-109. (PMID: 30230148)
Cancer Res Treat. 2016 Jul;48(3):990-7. (PMID: 26790967)
PLoS One. 2016 Apr 12;11(4):e0153286. (PMID: 27070544)
Oncotarget. 2018 May 22;9(39):25617-25629. (PMID: 29876012)
Anticancer Res. 2014 Apr;34(4):1953-8. (PMID: 24692731)
Anticancer Res. 2012 Aug;32(8):3357-62. (PMID: 22843915)
Cell Physiol Biochem. 2015;37(6):2393-404. (PMID: 26646579)
Nat Immunol. 2016 Jul 19;17(8):906-13. (PMID: 27434011)
Haematologica. 2012 Jul;97(7):980-8. (PMID: 22271892)
Support Care Cancer. 2013 May;21(5):1313-9. (PMID: 23196819)
Brain Res Rev. 2006 Aug;51(2):240-64. (PMID: 16388853)
Ther Clin Risk Manag. 2018 Apr 11;14:653-657. (PMID: 29695909)
HPB (Oxford). 2013 Nov;15(11):858-64. (PMID: 23458554)
J Pain. 2012 Mar;13(3):276-84. (PMID: 22325298)
Comp Med. 2015 Jun;65(3):196-201. (PMID: 26141444)
Pain. 2020 Feb;161(2):405-415. (PMID: 31634341)
Neuropharmacology. 2014 Apr;79:37-48. (PMID: 24225197)
J Surg Oncol. 2017 Dec;116(7):947-953. (PMID: 28876454)
Transfusion. 2003 May;43(5):609-13. (PMID: 12702182)
J Hepatol. 2013 Aug;59(2):318-26. (PMID: 23624001)
Biomed Res Int. 2019 Feb 18;2019:4650695. (PMID: 30906773)
Br J Radiol. 1999 Sep;72(861):906-10. (PMID: 10645201)
Vet Pathol. 2012 May;49(3):508-23. (PMID: 22262354)
Curr Opin Hematol. 2002 May;9(3):183-9. (PMID: 11953662)
J Oncol Pharm Pract. 2015 Apr;21(2):148-56. (PMID: 24500808)
J Exp Med. 1997 Feb 17;185(4):755-66. (PMID: 9034153)
Clin Colorectal Cancer. 2009 Oct;8(4):225-30. (PMID: 19822514)
Support Care Cancer. 2020 Oct;28(10):4781-4788. (PMID: 31974772)
Semin Oncol. 1998 Jun;25(3 Suppl 7):43-6. (PMID: 9671330)
Chem Res Toxicol. 2004 Oct;17(10):1391-7. (PMID: 15487901)
N Engl J Med. 2004 Jun 3;350(23):2343-51. (PMID: 15175436)
J Am Coll Surg. 2015 Mar;220(3):271-80. (PMID: 25617913)
Br J Cancer. 2016 Oct 11;115(8):e7. (PMID: 27632372)
Sci Rep. 2015 Oct 06;5:14756. (PMID: 26439902)
PLoS One. 2017 Jan 26;12(1):e0170814. (PMID: 28125674)
J Clin Oncol. 2010 May 20;28(15):2549-55. (PMID: 20406923)
Lancet Oncol. 2014 Oct;15(11):1245-53. (PMID: 25201358)
Histopathology. 2010 Mar;56(4):430-9. (PMID: 20459550)
HPB (Oxford). 2013 Aug;15(8):581-7. (PMID: 23458185)
J Clin Oncol. 2012 May 20;30(15):1805-12. (PMID: 22508807)
Cancer Cell. 2016 Apr 11;29(4):587-601. (PMID: 27070705)
Sci Rep. 2018 Jan 18;8(1):1126. (PMID: 29348549)
Nat Methods. 2012 Jul;9(7):671-5. (PMID: 22930834)
PLoS One. 2017 Oct 11;12(10):e0186250. (PMID: 29020118)

figshare 10.6084/m9.figshare.12831758; 10.6084/m9.figshare.12831782; 10.6084/m9.figshare.12831791; 10.6084/m9.figshare.12831794; 10.6084/m9.figshare.12831803

0 (Cytokines)
04ZR38536J (Oxaliplatin)

Date Created: 20200903 Date Completed: 20201029 Latest Revision: 20201029

20250114

PMC7467301

10.1371/journal.pone.0238164

32877416