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Determining the mechanisms of lapatinib-induced diarrhoea using a rat model

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Abstract

Introduction

Diarrhoea caused by treatment with receptor tyrosine kinase inhibitors (TKI) targeting Epidermal Growth Factor Receptors (EGFR) is an important clinical toxicity in oncology that remains poorly understood. This study aimed to identify histological and molecular changes within the intestine following lapatinib to elucidate mechanisms of diarrhoea related to treatment with this dual EGFR TKI.

Methods and materials

Male albino Wistar rats were orally gavaged lapatinib at 100, 240 or 500 mg/kg daily for 4 weeks and assessed for indicators of gastrointestinal injury at the end of each week. Lapatinib in combination with weekly paclitaxel (9 mg/kg i.p.) was also assessed for cumulative injury. At each time point, blood was collected for biochemical analysis. Sections or jejunum and colon were also collected and underwent immunohistochemistry and RT-PCR to detect markers of EGFR pathway signalling, and morphometric analysis to assess changes in mucosal architecture.

Results

Lapatinib (with or without paclitaxel co-treatment) caused dose-dependent changes in crypt length, mitotic rate and goblet cell morphology. Jejunal crypt expression of EGFR and ErbB2 were decreased, whilst no changes in Erk1/2 were observed. Markers of apoptosis (caspase-3) and proliferation (Ki-67) were only significantly altered in rats treated with both lapatinib and paclitaxel.

Conclusions

In our novel rat model of lapatinib-induced diarrhoea we have shown that changes in small intestinal morphometry and expression of EGFR are associated with diarrhoea. Further research is required to test intervention agents for the prevention of diarrhoea.

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References

  1. Metzger Filho O, Saini KS, Azim HA Jr, Awada A (2012) Prevention and management of major side effects of targeted agents in breast cancer. Crit Rev Oncol Hematol 84(Suppl 1):e79–e85

    Article  PubMed  Google Scholar 

  2. Melosky B (2012) Supportive care treatments for toxicities of anti-egfr and other targeted agents. Curr Oncol. 19(Suppl 1):S59–S63

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Keefe DM, Gibson RJ (2007) Mucosal injury from targeted anti-cancer therapy. Support Care Cancer 15(5):483–490

    Article  PubMed  Google Scholar 

  4. Goss PE, Smith IE, O’Shaughnessy J, Ejlertsen B, Kaufmann M, Boyle F et al (2013) Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised, controlled, phase 3 trial. Lancet Oncol. 14(1):88–96

    Article  CAS  PubMed  Google Scholar 

  5. Sequist LV, Besse B, Lynch TJ, Miller VA, Wong KK, Gitlitz B et al (2010) Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J Clin Oncol 28(18):3076–3083

    Article  CAS  PubMed  Google Scholar 

  6. Witta SE, Jotte RM, Konduri K, Neubauer MA, Spira AI, Ruxer RL et al (2012) Randomized phase II trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy. J Clin Oncol 30(18):2248–2255

    Article  CAS  PubMed  Google Scholar 

  7. Thomas SK, Fossella FV, Liu D, Schaerer R, Tsao AS, Kies MS et al (2006) Asian ethnicity as a predictor of response in patients with non-small-cell lung cancer treated with gefitinib on an expanded access program. Clin Lung Cancer. 7(5):326–331

    Article  CAS  PubMed  Google Scholar 

  8. Rusnak DW, Lackey K, Affleck K, Wood ER, Alligood KJ, Rhodes N et al (2001) The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 1(2):85–94

    CAS  PubMed  Google Scholar 

  9. Ryan Q, Ibrahim A, Cohen MH, Johnson J, Ko CW, Sridhara R et al (2008) FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist. 13(10):1114–1119

    Article  CAS  PubMed  Google Scholar 

  10. Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V et al (2009) Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 27(33):5538–5546

    Article  CAS  PubMed  Google Scholar 

  11. Breast cancer in Australia: an overview In: Australian Institute of Health and Welfare, National Breast and Ovarian Cancer Centre, Cancer Series 71, Cat. No. CAN67, 2012

  12. Youlden DR, Cramb SM, Dunn NA, Muller JM, Pyke CM, Baade PD (2012) The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol. 36(3):237–248

    Article  PubMed  Google Scholar 

  13. Burris HA 3rd (2004) Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist. 9(Suppl 3):10–15

    Article  CAS  PubMed  Google Scholar 

  14. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C et al (2012) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379(9816):633–640

    Article  CAS  PubMed  Google Scholar 

  15. Crown JP, Burris HA 3rd, Boyle F, Jones S, Koehler M, Newstat BO et al (2008) Pooled analysis of diarrhea events in patients with cancer treated with lapatinib. Breast Cancer Res Treat 112(2):317–325

    Article  CAS  PubMed  Google Scholar 

  16. Loriot Y, Perlemuter G, Malka D, Penault-Llorca F, Boige V, Deutsch E et al (2008) Drug insight: gastrointestinal and hepatic adverse effects of molecular-targeted agents in cancer therapy. Nat Clin Pract Oncol 5(5):268–278

    Article  CAS  PubMed  Google Scholar 

  17. Rasmussen AR, Viby NE, Hare KJ, Hartmann B, Thim L, Holst JJ et al (2010) The intestinotrophic peptide, GLP-2, counteracts the gastrointestinal atrophy in mice induced by the epidermal growth factor receptor inhibitor, erlotinib, and cisplatin. Dig Dis Sci 55(10):2785–2796

    Article  CAS  PubMed  Google Scholar 

  18. Hare KJ, Hartmann B, Kissow H, Holst JJ, Poulsen SS (2007) The intestinotrophic peptide, glp-2, counteracts intestinal atrophy in mice induced by the epidermal growth factor receptor inhibitor, gefitinib. Clin Cancer Res 13(17):5170–5175

    Article  CAS  PubMed  Google Scholar 

  19. Yusta B, Holland D, Koehler JA, Maziarz M, Estall JL, Higgins R et al (2009) ErbB signaling is required for the proliferative actions of GLP-2 in the murine gut. Gastroenterology 137(3):986–996

    Article  CAS  PubMed  Google Scholar 

  20. McCole DF, Barrett KE (2009) Decoding epithelial signals: critical role for the epidermal growth factor receptor in controlling intestinal transport function. Acta Physiol (Oxf). 195(1):149–159

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Apfel SC (2000) Managing the neurotoxicity of paclitaxel (Taxol) and docetaxel (Taxotere) with neurotrophic factors. Cancer Invest 18(6):564–573

    Article  CAS  PubMed  Google Scholar 

  22. Bowen JM, Mayo BJ, Plews E, Bateman E, Stringer AM, Boyle FM et al (2012) Development of a rat model of oral small molecule receptor tyrosine kinase inhibitor-induced diarrhea. Cancer Biol Ther 13(13):1269–1275

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Cummins AG, LaBrooy JT, Stanley DP, Rowland R, Shearman DJ (1990) Quantitative histological study of enteropathy associated with HIV infection. Gut 31(3):317–321

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Stringer AM, Gibson RJ, Logan RM, Bowen JM, Yeoh AS, Hamilton J et al (2009) Gastrointestinal microflora and mucins may play a critical role in the development of 5-Fluorouracil-induced gastrointestinal mucositis. Exp Biol Med (Maywood). 234(4):430–441

    Article  CAS  PubMed  Google Scholar 

  25. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408

    Article  CAS  PubMed  Google Scholar 

  26. Demirci U, Buyukberber S, Yilmaz G, Kerem M, Coskun U, Uner A et al (2012) Hepatotoxicity associated with lapatinib in an experimental rat model. Eur J Cancer 48(2):279–285

    CAS  PubMed  Google Scholar 

  27. Burris HA 3rd, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O’Neil B et al (2005) Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23(23):5305–5313

    Article  CAS  PubMed  Google Scholar 

  28. Barcelo A, Claustre J, Moro F, Chayvialle JA, Cuber JC, Plaisancié P (2000) Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon. Gut 46(2):218–224

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Phillips TE, Phillips TH, Neutra MR (1984) Regulation of intestinal goblet cell secretion. IV. Electrical field stimulation in vitro. Am J Physiol. 247(6 Pt 1):G682–G687

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Acknowledgments

We acknowledge Jocelyn Darby for technical assistance with the animal studies.

Conflict of interest

Funding to complete the studies herein was administered as an unrestricted educational grant from GlaxoSmithKline to MedVet Sciences, on behalf of the Royal Adelaide Hospital. The role of the funding source was to provide study drug, lapatinib, and support to complete the animal experiment. The chief investigator named on the grant was Professor Keefe. No honorarium was received by any author.

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Authors and Affiliations

  1. School of Medical Sciences, University of Adelaide, Adelaide, 5005, Australia

    Joanne M. Bowen

  2. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia

    Bronwen J. Mayo & Andrea M. Stringer

  3. School of Medicine, University of Adelaide, Adelaide, Australia

    Erin Plews, Emma Bateman, Anthony Wignall & Dorothy M. K. Keefe

  4. Sydney Medical School (Northern), University of Sydney, Sydney, Australia

    Frances M. Boyle

  5. Hanson Institute, SA Pathology, Adelaide, Australia

    Dorothy M. K. Keefe

  6. Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, Australia

    Dorothy M. K. Keefe

Authors
  1. Joanne M. Bowen
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  2. Bronwen J. Mayo
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  3. Erin Plews
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  4. Emma Bateman
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  8. Dorothy M. K. Keefe
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Correspondence to Joanne M. Bowen.

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Bowen, J.M., Mayo, B.J., Plews, E. et al. Determining the mechanisms of lapatinib-induced diarrhoea using a rat model. Cancer Chemother Pharmacol 74, 617–627 (2014). https://doi.org/10.1007/s00280-014-2519-4

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  • DOI: https://doi.org/10.1007/s00280-014-2519-4

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