Intestinal response to myeloablative chemotherapy in piglets
Abstract
Chemotherapy-induced myeloablation prior to allogeneic hematopoietic stem cell transplantation (HSCT) may be associated with severe toxicity. The current understanding of the pathophysiology of oral and gastrointestinal (GI) toxicity is largely derived from studies in rodents and very little is known from humans, especially children. We hypothesized that milk-fed piglets can be used as a clinically relevant model of GI-toxicity related to a standard conditioning chemotherapy (intravenous busulfan, Bu plus cyclophosphamide, Cy) used prior to HSCT. In study 1, dose–response relationships were investigated in three-day-old pigs (Landrace × Yorkshire × Duroc, n = 6). Pigs were given one of three different dose combinations of Bu and Cy (A: 4 days Bu, 2 × 1.6 mg/kg plus 2 days Cy, 60 mg/kg; B: 4 days Bu, 2 × 0.8 mg/kg plus 2 days Cy, 30 mg/kg; C: 2 days Bu at 2 × 1.6 mg/kg plus 1 day Cy, 60 mg/kg) and bone marrow was collected on day 11. Histology of bone marrow samples showed total aplasia after treatment A. Using this treatment in study 2, Bu–Cy pigs showed lowered spleen and intestinal weights and variable clinical signs of dehydration, sepsis, and pneumonia at tissue collection. Oral mucositis was evident as ulcers in the soft palate in 4/9 Bu–Cy pigs and villus height and brush-border enzyme activities were reduced, especially in the proximal intestine. There were no consistent effects on tissue cytokine levels (IL-8, IL-6, IL-1β, TNF-α) or blood chemistry values (electrolytes, liver transaminases, bilirubin, alkaline phosphatase), except that blood iron levels were higher in Bu–Cy pigs. We conclude that a myeloablative Bu–Cy regimen to piglets results in clinical signs comparable to those seen in pediatric patients subjected to myeloablative treatment prior to HSCT. Piglets may be used as a model for investigating chemotherapy-induced toxicity and dietary and medical interventions.
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References
1. Sonis ST. Regimen-related gastrointestinal toxicities in cancer patients. Curr Opin Support Palliat Care 2010; 4: 26–30.
2. Silverman S Jr. Diagnosis and management of oral mucositis. J Support Oncol 2007; 5: 13–21.
3. Bowen JM, Gibson RJ, Keefe DMK. Animal models of mucositis: Implications for therapy. J Support Oncol 2011; 9: 161–8.
4. Keefe DM. Gastrointestinal mucositis: A new biological model. Support Care Cancer 2004; 12: 6–9.
5. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer 2004; 4: 277–84.
6. Bowen JM, Keefe DM. New pathways for alimentary mucositis. J Oncol 2008; 907892.
7. Sonis ST, Lindquist L, Van Vugt A, Stewart AA, Stam K, Qu G-Y, Iwata KK, Haley JD. Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor β3. Cancer Res 1994; 54: 1135–8.
8. Gibson RJ, Keefe DMK, Thompson FM, Clarke JM, Goland GJ, Cummins AG. Effect of interleukin-11 on ameliorating intestinal damage after methotrexate treatment of breast cancer in rats. Digest Dis Sci 2002; 47: 2751–7.
9. Farrell CL, Bready JV, Rex KL, Chen JN, DiPalma CR, Whitcomb KL, Yin S, Hill DC, Wiemann B, Starnes CO, Havill AM, Lu Z-N, Aukerman SL, Pierce GF, Thomason A, Potten CS, Ulich TR, Lacey DL. Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality. Cancer Res 1998; 58: 933–9.
10. Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, Migliorati CA, McGuire DB, Hutchins RD, Peterson DE. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 2007; 109: 820–31.
11. Worthington HV, Clarkson JE, Bryan G, Furness S, Glenny AM, Littlewood A, McCabe MG, Meyer S, Khalid T. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2011; (4): CD000978–CD000978.
12. Miller ER, Ullrey DE. The pig as a model for human nutrition. Ann Rev Nutr 1987; 7: 361–82.
13. Swindle MM, Makin A, Herron AJ, Clubb FJ, Frazier KS. Swine as models in biomedical research and toxicology testing. Vet Pathol 2012; 49: 344–56.
14. Meurens F, Summerfield A, Nauwynck H, Saif L, Gerdts V. The pig: A model for human infectious diseases. Trends Microbiol 2012; 20: 50–7.
15. Turpeinen M, Ghiciuc C, Opritoui M, Tursas L, Pelkonen O, Pasanen M. Predictive value of animal models for human cytochrome p450 (cyp)-mediated metabolism: A comparative study in vitro. Xenobiotica 2007; 37: 1367–77.
16. Wernersson R, Schierup MH, Jørgensen FG, Gorodkin J, Panitz F, Staerfeldt H-H, Christensen OF, Mailund T, Hornshøj H, Klein A, Wang J, Liu B, Hu S, Dong W, Li W, Wong GKS, Yu J, Wang J, Bendixen C, Fredholm M, Brunak S, Yang H, Bolund L. Pigs in sequence space: A 0.66x coverage pig genome survey based on shotgun sequencing. BMC Genomics 2005; 6: 70–70.
17. Manzano M, Bueno P, Rueda R, Ramirez-Tortosa CL, Prieto Pa, Lopez-Pedrosa JM. Intestinal toxicity induced by 5-fluorouracil in pigs: A new preclinical model. Chemotherapy 2007; 53: 344–55.
18. Bjornvad CR, Thymann T, Deutz NE, Burrin DG, Jensen SK, Jensen BB, Molbak L, Boye M, Larsson LI, Schmidt M, Michaelsen KF, Sangild PT. Enteral feeding induces diet-dependent mucosal dysfunction, bacterial proliferation, and necrotizing enterocolitis in preterm pigs on parenteral nutrition. Am J Physiol Gastrointest Liver Physiol 2008; 295: G1092–103.
19. Kashyap A, Wingard J, Cagnoni P, Jones R, Tarantolo S, Hu W, Blume K, Niland J, Palmer JM, Vaughan W, Fernandez H, Champlin R, Forman S, Andersson BS. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: Decreased incidence of hepatic venoocclusive disease (hvod), hvod-related mortality, and overall 100-day mortality. Biol Blood Marrow Transplant 2002; 8: 493–500.
20. Hows JM, Mehta A, Ward L, Woods K, Perez R, Gordon MY, Gordon-Smith EC. Comparison of mesna with forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplantation: A prospective randomised study. Br J Cancer 1984; 50: 753–6.
21. Bollen PJA, Hansen AK, Rasmussen HJ, Suckow MA. The laboratory swine, Boca Raton: CRC Press, 2000.
22. Thymann T, Burrin DG, Tappenden KA, Bjornvad CR, Jensen SK, Sangild PT. Formula-feeding reduces lactose digestive capacity in neonatal pigs. Br J Nutr 2006; 95: 1075–81.
23. Hessels J, Snoeyink EJ, Platenkamp AJ, Voortman G, Steggink J, Eidhof HH. Assessment of intestinal permeability: Enzymatic determination of urinary mannitol, raffinose, sucrose and lactose on hitachi analyzer. Clin Chem Lab Med 2003; 41: 33–8.
24. Sangild PT, Petersen YM, Schmidt M, Elnif J, Petersen TK, Buddington RK, Greisen G, Michaelsen KF, Burrin DG. Preterm birth affects the intestinal response to parenteral and enteral nutrition in newborn pigs. J Nutr 2002; 132: 2673–81.
25. Sangild PT, Sjostrom H, Noren O, Fowden AL, Silver M. The prenatal development and glucocorticoid control of brush-border hydrolases in the pig small intestine. Pediatr Res 1995; 37: 207–12.
26. Mitchell EP. Gastrointestinal toxicity of chemotherapeutic agents. Semin Oncol 2006; 33: 106–20.
27. Sonis ST. Mucositis: The impact, biology and therapeutic opportunities of oral mucositis. Oral Oncol 2009; 45: 1015–20.
28. van Vliet MJ, Harmsen HJM, de Bont ESJM, Tissing WJE. The role of intestinal microbiota in the development and severity of chemotherapy-induced mucositis. PLoS Pathog 2010; 6: e1000879–e1000879.
29. Godlewski MM, Slazak P, Zabielski R, Piastowska A, Gralak MA. Quantitative study of soybean-induced changes in proliferation and programmed cell death in the intestinal mucosa of young rats. J Physiol Pharmacol 2006; 57: 125–33.
30. van der Velden WJ, Blijlevens NM, Feuth T, Donnelly JP. Febrile mucositis in haematopoietic sct recipients. Bone Marrow Transplant 2009; 43: 55–60.
31. Keefe DM, Brealey J, Goland GJ, Cummins AG. Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut 2000; 47: 632–7.
32. Cunningham D, Morgan RJ, Mills PR, Nelson LM, Toner PG, Soukop M, McArdle CS, Russell RI. Functional and structural changes of the human proximal small intestine after cytotoxic therapy. J Clin Pathol 1985; 38: 265–70.
33. Kissow H, Viby NE, Hartmann B, Holst JJ, Timm M, Thim L, Poulsen SS. Exogenous glucagon-like peptide-2 (glp-2) prevents chemotherapy-induced mucositis in rat small intestine. Cancer Chemother Pharmacol 2012; 70: 39–48.
34. Fijlstra M, Rings EH, Verkade HJ, van Dijk TH, Kamps WA, Tissing WJ. Lactose maldigestion during methotrexate-induced gastrointestinal mucositis in a rat model. Am J Physiol Gastrointest Liver Physiol 2011; 300: G283–91.
35. Johansson JE, Ekman T. Gastro-intestinal toxicity related to bone marrow transplantation: Disruption of the intestinal barrier precedes clinical findings. Bone Marrow Transplant 1997; 19: 921–5.
36. Al-Mousa H, Al-Shammari Z, Al-Ghonaium A, Al-Dhekri H, Al-Muhsen S, Al-Saud B, Arnaout R, Al-Seraihy A, Al-Jefri A, Al-Ahmari A, Ayas M, El-Solh H. Allogeneic stem cell transplantation using myeloablative and reduced-intensity conditioning in patients with major histocompatibility complex class ii deficiency. Biol Blood Marrow Transplant 2010; 16: 818–23.
37. Yuen KY, Woo PC, Hui CH, Luk WK, Chen FE, Lie AK, Liang R. Unique risk factors for bacteraemia in allogeneic bone marrow transplant recipients before and after engraftment. Bone Marrow Transplant 1998; 21: 1137–43.
38. Blijlevens NMA, Donnelly JP, Pauw BED. Mucosal barrier injury: Biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: An overview. Bone Marrow Transplant 2000; 7: 1269–78.
39. Andreassen BU, Paerregaard a, Michaelsen KF, Andersen J, Heilmann CJ, Müller K. Nutrition, anthropometry, gastrointestinal dysfunction, and circulating levels of tumour necrosis factor alpha receptor i and interleukin-1 receptor antagonist in children during stem cell transplantation. Pediatric Transplant 2009; 13: 182–7.
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Article first published online: December 4, 2013
Issue published: January 2014
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All authors participated in the design, interpretation of the studies and analysis of the data and review of the manuscript. PLP, RLS, and TT conducted the experiments, BLP evaluated bone marrows, and PLP, RLS, and PTS wrote the manuscript.
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This article was published in Experimental Biology and Medicine.
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