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01-03-2019 | Original Article

Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model

Authors: Kate R. Secombe, Imogen A. Ball, Joseph Shirren, Anthony D. Wignall, John Finnie, Dorothy Keefe, Francesca Avogadri-Connors, Elizabeth Olek, David Martin, Susan Moran, Joanne M. Bowen

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2019

Abstract

Purpose

Neratinib is an irreversible pan-ErbB tyrosine kinase inhibitor used for the extended adjuvant treatment of early-stage HER2-positive breast cancer. Its use is associated with the development of severe diarrhea in up to 40% of patients in the absence of proactive management. We previously developed a rat model of neratinib-induced diarrhea and found inflammation and anatomical disruption in the ileum and colon. Here we tested whether anti-diarrheal interventions, budesonide and colesevelam, can reduce neratinib-induced diarrhea and intestinal pathology.

Methods

Rats were treated with 50 mg/kg neratinib via oral gavage for 14 or 28 days (total n = 64). Body weight and diarrhea severity were recorded daily. Apoptosis was measured using immunohistochemistry for caspase-3. Inflammation was measured via a multiplex cytokine/chemokine assay. ErbB levels were measured using PCR and Western Blot.

Results

Budesonide co-treatment caused rats to gain significantly less weight than neratinib alone from day 4 of treatment (P = 0.0418). Budesonide (P = 0.027) and colesevelam (P = 0.033) each reduced the amount of days with moderate diarrhea compared to neratinib alone. In the proximal colon, rats treated with neratinib had higher levels of apoptosis compared to controls (P = 0.0035). Budesonide reduced histopathological injury in the proximal (P = 0.0401) and distal colon (P = 0.027) and increased anti-inflammatory IL-4 tissue concentration (ileum; P = 0.0026, colon; P = 0.031) compared to rats treated with neratinib alone. In the distal ileum, while budesonide decreased ErbB1 mRNA expression compared to controls (P = 0.018) (PCR), an increase in total ErbB1 protein was detected (P = 0.0021) (Western Blot).

Conclusion

Both budesonide and colesevelam show potential as effective interventions against neratinib-induced diarrhea.

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Cherian MA, Ma CX (2017) The role of neratinib in HER2-driven breast cancer. Future Oncol 13 (22):1931–1943. https://doi.org/10.2217/fon-2017-0186 (Epub ahead of print) CrossRef

Kourie HR, El Rassy E, Clatot F, de Azambuja E, Lambertini M (2017) Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib. Onco Targets Ther 10:3363–3372. https://doi.org/10.2147/ott.s122397 CrossRefPubMedPubMedCentral

Echavarria I, Lopez-Tarruella S, Marquez-Rodas I, Jerez Y, Martin M (2017) Neratinib for the treatment of HER2-positive early stage breast cancer. Expert Rev Anticancer Ther 17(8):669–679. https://doi.org/10.1080/14737140.2017.1338954 CrossRefPubMed

Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, Silovski T, Gokmen E, von Minckwitz G, Ejlertsen B, Chia SK, Mansi J, Barrios CH, Gnant M, Buyse M, Gore I, Smith J 2nd, Harker G, Masuda N, Petrakova K, Zotano AG, Iannotti N, Rodriguez G, Tassone P, Wong A, Bryce R, Ye Y, Yao B, Martin M (2016) Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17(3):367–377. https://doi.org/10.1016/s1470-2045(15)00551-3 CrossRefPubMed

Park JW, Liu MC, Yee D, Yau C, van ‘t Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA (2016) Adaptive randomization of neratinib in early breast cancer. N Engl J Med 375(1):11–22. https://doi.org/10.1056/NEJMoa1513750 CrossRefPubMedPubMedCentral

Hurvitz S, Chan A, Iannotti N, Ibrahim E, Chien J, Chan N, Kellum A, Hansen V, Marx G, Kendall SD, Wilkinson M, Castrellon A, Ruiz R, Fang P, Hunt D, Moran S, Olek E, Barcenas CH (2017) Rugo HS Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2 + early-stage breast cancer: the control trial. In: San Antonio Breast Cancer Summit, San Antonio

McQuade RM, Stojanovska V, Abalo R, Bornstein JC, Nurgali K (2016) Chemotherapy-induced constipation and diarrhea: pathophysiology, current and emerging treatments. Front Pharmacol 7:414. https://doi.org/10.3389/fphar.2016.00414 CrossRefPubMedPubMedCentral

Upadhyay A, Bodar V, Malekzadegan M, Singh S, Frumkin W, Mangla A, Doshi K (2016) Loperamide Induced Life Threatening Ventricular Arrhythmia. Case Rep Cardiol 2016:5040176. https://doi.org/10.1155/2016/5040176 PubMedPubMedCentralCrossRef

Marraffa JM, Holland MG, Sullivan RW, Morgan BW, Oakes JA, Wiegand TJ, Hodgman MJ (2014) Cardiac conduction disturbance after loperamide abuse. Clin Toxicol (Phila) 52(9):952–957. https://doi.org/10.3109/15563650.2014.969371 CrossRef

10.

Karthaus M, Ballo H, Abenhardt W, Steinmetz T, Geer T, Schimke J, Braumann D, Behrens R, Behringer D, Kindler M, Messmann H, Boeck HP, Greinwald R, Kleeberg U (2005) Prospective, double-blind, placebo-controlled, multicenter, randomized phase III study with orally administered budesonide for prevention of irinotecan (CPT-11)-induced diarrhea in patients with advanced colorectal cancer. Oncology 68(4–6):326–332. https://doi.org/10.1159/000086971 CrossRefPubMed

11.

Kwapisz L, Jairath V, Khanna R, Feagan B (2017) Pharmacokinetic drug evaluation of budesonide in the treatment of Crohn’s disease. Expert Opin Drug Metab Toxicol 13(7):793–801. https://doi.org/10.1080/17425255.2017.1340454 CrossRefPubMed

12.

Stein A, Voigt W, Jordan K (2010) Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol 2(1):51–63. https://doi.org/10.1177/1758834009355164 CrossRefPubMedPubMedCentral

13.

Martinez-Moya P, Ortega-Gonzalez M, Gonzalez R, Anzola A, Ocon B, Hernandez-Chirlaque C, Lopez-Posadas R, Suarez MD, Zarzuelo A, Martinez-Augustin O, Sanchez de Medina F (2012) Exogenous alkaline phosphatase treatment complements endogenous enzyme protection in colonic inflammation and reduces bacterial translocation in rats. Pharmacol Res 66(2):144–153. https://doi.org/10.1016/j.phrs.2012.04.006 CrossRefPubMed

14.

Beigel F, Teich N, Howaldt S, Lammert F, Maul J, Breiteneicher S, Rust C, Goke B, Brand S, Ochsenkuhn T (2014) Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn’s disease: a randomized, double-blind, placebo-controlled study. J Crohns Colitis 8(11):1471–1479. https://doi.org/10.1016/j.crohns.2014.05.009 CrossRefPubMed

15.

Bowen JM, Mayo BJ, Plews E, Bateman E, Stringer AM, Boyle FM, Finnie JW, Keefe DM (2012) Development of a rat model of oral small molecule receptor tyrosine kinase inhibitor-induced diarrhea. Cancer Biol Ther 13(13):1269–1275. https://doi.org/10.4161/cbt.21783 CrossRefPubMedPubMedCentral

16.

Howarth GS, Francis GL, Cool JC, Xu X, Byard RW, Read LC (1996) Milk growth factors enriched from cheese whey ameliorate intestinal damage by methotrexate when administered orally to rats. J Nutr 126(10):2519–2530CrossRefPubMed

17.

Wardill HR, Gibson RJ, Van Sebille YZ, Secombe KR, Coller JK, White IA, Manavis J, Hutchinson MR, Staikopoulos V, Logan RM, Bowen JM (2016) Irinotecan-induced gastrointestinal dysfunction and pain are mediated by common TLR4-dependent mechanisms. Mol Cancer Ther 15(6):1376–1386. https://doi.org/10.1158/1535-7163.mct-15-0990 CrossRefPubMed

18.

Boue S, Fortgang I, Levy RJ Jr, Bhatnagar D, Burow M, Fahey G, Heiman ML (2016) A novel gastrointestinal microbiome modulator from soy pods reduces absorption of dietary fat in mice. Obesity (Silver Spring) 24(1):87–95. https://doi.org/10.1002/oby.21197 CrossRef

19.

Sann H, Erichsen J, Hessmann M, Pahl A, Hoffmeyer A (2013) Efficacy of drugs used in the treatment of IBD and combinations thereof in acute DSS-induced colitis in mice. Life Sci 92(12):708–718. https://doi.org/10.1016/j.lfs.2013.01.028 CrossRefPubMed

20.

Ocon B, Aranda CJ, Gamez-Belmonte R, Suarez MD, Zarzuelo A, Martinez-Augustin O, Sanchez de Medina F (2016) The glucocorticoid budesonide has protective and deleterious effects in experimental colitis in mice. Biochem Pharmacol 116:73–88. https://doi.org/10.1016/j.bcp.2016.07.010 CrossRefPubMed

21.

Fischer A, Gluth M, Weege F, Pape UF, Wiedenmann B, Baumgart DC, Theuring F (2014) Glucocorticoids regulate barrier function and claudin expression in intestinal epithelial cells via MKP-1. Am J Physiol Gastrointest Liver Physiol 306(3):G218–G228. https://doi.org/10.1152/ajpgi.00095.2013 CrossRefPubMed

22.

Van Sebille YZA, Gibson RJ, Wardill HR, Secombe KR, Ball IA, Keefe DMK, Finnie JW, Bowen JM (2017) Dacomitinib-induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats. Int J Cancer J I du Cancer 140(12):2820–2829. https://doi.org/10.1002/ijc.30699 CrossRef

23.

Gibson RJ, Bowen JM, Cummins AG, Keefe DM (2005) Relationship between dose of methotrexate, apoptosis, p53/p21 expression and intestinal crypt proliferation in the rat. Clin Exp Med 4(4):188–195. https://doi.org/10.1007/s10238-004-0055-y CrossRefPubMed

24.

Dawson PA, Lan T, Rao A (2009) Bile acid transporters. J Lipid Res 50(12):2340–2357. https://doi.org/10.1194/jlr.R900012-JLR200 CrossRefPubMedPubMedCentral

25.

Krag E, Krag B (1976) Regional ileitis (Crohn’s disease). I. Kinetics of bile acid absorption in the perfused ileum. Scand J Gastroenterol 11(5):481–486PubMed

26.

Stelzner M, Somasundaram S, Khakberdiev T (2001) Systemic effects of acute terminal ileitis on uninflamed gut aggravate bile acid malabsorption. J Surg Res 99(2):359–364. https://doi.org/10.1006/jsre.2001.6137 CrossRefPubMed

27.

Jung D, Fantin AC, Scheurer U, Fried M, Kullak-Ublick GA (2004) Human ileal bile acid transporter gene ASBT (SLC10A2) is transactivated by the glucocorticoid receptor. Gut 53(1):78–84CrossRefPubMedPubMedCentral

28.

Bowen JM (2013) Mechanisms of TKI-induced diarrhea in cancer patients. Curr Opin Support Palliat Care 7(2):162–167. https://doi.org/10.1097/SPC.0b013e32835ec861 CrossRefPubMed

29.

Abbas R, Hug BA, Leister C, Sonnichsen D (2012) A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor. Cancer Chemother Pharmacol 70(1):191–199. https://doi.org/10.1007/s00280-012-1857-3 CrossRefPubMed

30.

Barkas F, Liberopoulos E, Kei A, Elisaf M (2013) Electrolyte and acid-base disorders in inflammatory bowel disease. Ann Gastroenterol 26(1):23–28PubMedPubMedCentral

31.

Priyamvada S, Gomes R, Gill RK, Saksena S, Alrefai WA, Dudeja PK (2015) Mechanisms underlying dysregulation of electrolyte absorption in inflammatory bowel disease-associated diarrhea. Inflamm Bowel Dis 21(12):2926–2935. https://doi.org/10.1097/mib.0000000000000504 CrossRefPubMedPubMedCentral

32.

Gordon PV, Price WA, Stiles AD, Rutledge JC (2001) Early postnatal dexamethasone diminishes transforming growth factor alpha localization within the ileal muscularis propria of newborn mice and extremely low-birth-weight infants. Pediatr Dev Pathol 4(6):532–537CrossRefPubMed

33.

Cyr MM, Baatjes AJ, Dorman SC, Crawford L, Sehmi R, Foley R, Alam R, Byrne PO, Denburg JA (2008) In vitro effects of budesonide on eosinophil-basophil lineage commitment. Open Respir Med J 2:60–66. https://doi.org/10.2174/1874306400802010060 CrossRefPubMedPubMedCentral

34.

West GA, Matsuura T, Levine AD, Klein JS, Fiocchi C (1996) Interleukin 4 in inflammatory bowel disease and mucosal immune reactivity. Gastroenterology 110(6):1683–1695CrossRefPubMed

35.

Kole A, Maloy KJ (2014) Control of intestinal inflammation by interleukin-10. Curr Top Microbiol Immunol 380:19–38. https://doi.org/10.1007/978-3-662-43492-5_2 PubMedCrossRef

36.

Beaurepaire C, Smyth D, McKay DM (2009) Interferon-gamma regulation of intestinal epithelial permeability. J Interferon Cytokine Res 29(3):133–144. https://doi.org/10.1089/jir.2008.0057 CrossRefPubMed

37.

Nava P, Koch S, Laukoetter MG, Lee WY, Kolegraff K, Capaldo CT, Beeman N, Addis C, Gerner-Smidt K, Neumaier I, Skerra A, Li L, Parkos CA, Nusrat A (2010) Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways. Immunity 32(3):392–402. https://doi.org/10.1016/j.immuni.2010.03.001 CrossRefPubMedPubMedCentral

Title: Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model
Authors: Kate R. Secombe
Imogen A. Ball
Joseph Shirren
Anthony D. Wignall
John Finnie
Dorothy Keefe
Francesca Avogadri-Connors
Elizabeth Olek
David Martin
Susan Moran
Joanne M. Bowen
Publication date: 01-03-2019
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-018-3756-8

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