The protective effect of sildenafil on liver sinusoidal obstructive syndrome after oxaliplatin-based chemotherapy: An experimental animal study

Year 2020, , 587 - 591, 01.07.2020

Mustafa Taner Bostancı , İbrahim Yılmaz , Mehmet Saydam , Hakan Uzunoğlu Gülden Aydog Koray Koşmaz , Erdal Bostancı

https://doi.org/10.28982/josam.679489

Abstract

Aim: Sinusoidal obstructive syndrome (SOS) that develops due to oxaliplatin-based chemotherapy influences morbidity and mortality following surgical treatment of colorectal liver metastases. The aim of this study was to evaluate the protective effect of sildenafil on liver damage (sinusoidal obstructive syndrome (SOS)) that develops due to oxaliplatin-based chemotherapy.
Methods: An experimental animal study was conducted and a total of 42 rats were randomly separated into 4 groups as Sham, intraperitoneal chemotherapy (ipCT), ipCT+low-dose sildenafil treatment, and ipCT +high-dose sildenafil treatment. The ipCT was applied once a week for 5 weeks. Histochemical analysis was made in the livers removed from rats.
Results: Parenchymal, stromal, and vascular changes were examined, and no statistically significant difference was determined between the groups with respect to the severity of sinusoidal dilatation (P=0.243). The groups significantly differed with regards to centrilobular, peliotic changes and hepatocellular changes (P<0.001).
Conclusion: Sildenafil has a protective effect against liver damage that develops due to oxaliplatin-based chemotherapy and prevents the development of SOS during chemotherapy in colorectal cancer patients. Therefore, it could be considered as a treatment strategy.

Keywords

Oxaliplatin, Sinusoidal obstructive syndrome, Sildenafil, Colorectal cancer, Liver metastasis

Sildenafil'in oksaliplatin esaslı kemoterapi sonrası karaciğerde gelişen sinüsoidal obstruktif sendrom üzerine koruyucu etkisi: Deneysel bir hayvan çalışması

Abstract

Amaç: Oksaliplatin bazlı kemoterapinin karaciğer metastazlı kolon kanserli hastalarda kullanımı karaciğer hasarına (sinüsoidal obstruktif sendrom (SOS)) neden olarak; metastaz rezeksiyonu sonrasında mortalite ve morbiditeyi arttırır. Bu çalışmamızda; sildenafilin kolorektal kanserlerin karaciğer metastazları için oksaliplatin bazlı kemoterapi sonucunda gelişen karaciğer hasarı, (SOS) üzerindeki koruyucu etkisini değerlendirmeyi amaçladık.
Yöntemler: Deneysel bir hayvan çalışması yürütüldü ve toplam 42 rat rastgele Sham, intraperitoneal kemoterapi (ipCT), ipCT + düşük doz sildenafil tedavisi ve ipCT +yüksek doz sildenafil tedavi grupları olarak 4 gruba ayrıldı. İpCT, 5 haftalık bir süre boyunca haftada birkez uygulandı. Ratlardan çıkarılan karaciğerlerde histopatolojik analiz yapıldı.
Bulgular: Parankimal, stromal ve vasküler değişiklikler incelendi ve sinüzoidal dilatasyonun şiddeti açısından gruplar arasında istatistiksel olarak anlamlı bir fark bulunmadı (P=0,243). Dört grup arasında sentrolobüler değişiklikler açısından istatistiksel olarak anlamlı fark saptandı (P<0,001). Peliotik ve hepatosellüler değişikliklerin değerlendirilmesinde gruplar arasındaki fark istatistiksel olarak anlamlı bulundu (P<0,001).
Sonuç: Sildenafil, kolorektal kanser hastalarında kemoterapi sırasında oksaliplatin bazlı kemoterapinin bir sonucu olarak gelişen SOS gelişimini önleyerek karaciğer hasarına karşı koruyucu bir etkiye sahip olması nedeniyle, kemoterapi esnasında tedaviye eklenmelidir.

Keywords

Oxaliplatin, Sinüsoidal obstrüktif sendrom, Sildenafil, Kolorektal kanser, Karaciğer metastaz

References

• 1. Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influencing the natural history of colorectal liver metastases. Lancet. 1994;343:1405–10.
• 2. Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27:3677–83.
• 3. Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg. 2004;240:644–57.
• 4. Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, et.al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377:2103–14.
• 5. de Meijer VE, Kalish BT, Puder M, Ijzermans JNM. Systematic review and meta-analysis of steatosis as a risk factor in major hepatic resection. Br J Surg. 2010;201097:1331–9.
• 6. Robinson SM, Mann J, Manas DM, Mann DA, White SA. An experimental study to identify the potential role of pharmacogenomics in determining the occurrence of oxaliplatin-induced liver injury. HPB. 2013;15:581-7.
• 7. Gökakın AK, Atabey M, Deveci K, Sancakdar E, Tuzcu M, Duger C, et al. The effects of sildenafil in liver and kidney injury in a rat model of severe scald burn: a biochemical and histopathological study. Ulus Travma Acil Cerrahi Derg. 2014;20:319-27.
• 8. Robinson SM, Mann DA, Manas DM, Oakley F, Mann J, White SA. The potential contribution of tumour-related factors to the development of FOLFOX-induced sinusoidal obstruction syndrome. Br J Cancer. 2013;109:2396-403.
• 9. Tamandl D, Klinger M, Eipeldauer S, Herberger B, Kaczirek K, Gruenberger B, et al. Sinusoidal obstruction syndrome impairs long-term outcome of colorectal liver metastases treated with resection after neoadjuvant chemotherapy. Ann Surg Oncol. 2011;18:421–30.
• 10. Soubrane O, Brouquet A, Zalinski S, Terris B, Brézault C, Mallet V, et al. Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome. Ann Surg. 2010;251:454–60.
• 11. Hubert C, Sempoux C, Humblet Y, van den Eynde M, Zech F, Leclercq I, et al. Sinusoidal obstruction syndrome (SOS) related to chemotherapy for colorectal liver metastases: factors predictive of severe SOS lesions and protective effect of bevacizumab. HPB. 2013;15:858-64.
• 12. Vreuls CP, Van Den Broek MA, Winstanley A, Koek GH, Wisse E, Dejong CH, et al. Hepatic sinusoidal obstruction syndrome (SOS) reduces the effect of oxaliplatin in colorectal liver metastases. Histopathology. 2012;61:314–8.
• 13. Deleve LD, Wang X, Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology. 2008;48:920–30.
• 14. McCuskey RS. Sinusoidal endothelial cells as an early target for hepatic toxicants. Clin Hemorheol Microcirc. 2006;34(1–2):5–10.
• 15. Fan CQ, Crawford JM. Sinusoidal obstruction syndrome (hepatic veno-occlusive disease). J Clin Exp Hepatol. 2014;4:332-46.
• 16. DeLeve LD, Wang X. Decrease in nitric oxide production contributes to hepatic venoocclusive disease. Hepatology. 1999;30:218.
• 17. DeLeve LD, Wang X, Kanel GC, Ito Y, Bethea NW, McCuskey MK, et al. Decreased hepatic nitric oxide production contributes to the development of rat sinusoidal obstruction syndrome. Hepatology. 2003;38:900–08.
• 18. Deleve LD, Wang X, Tsai J, Kanel G, Strasberg S, Tokes ZA. Sinusoidal obstruction syndrome (veno-occlusive disease) in the rat is prevented by matrix metalloproteinase inhibition. Gastroenterology. 2003;125:882–90.
• 19. Goringe AP, Brown S, O’Callaghan U, Rees J, Jebb S, Elia M, et al. Glutamine and vitamin E in the treatment of hepatic veno-occlusive disease following high-dose chemotherapy. Bone Marrow Transplant. 1998;21:829–32.
• 20. Klinger M, Eipeldauer S, Hacker S, Herberger B, Tamandl D, Dorfmeister M, et al. Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases. Eur J Surg Oncol. 2009;35:515–20.
• 21. DeLeve LD, Valla D, Garcia-Tsao G. Vascular disorders of the liver. Hepatology. 2009;49:1729–64.
• 22. Kweekel DM, Gelderblom H, Guchelaar HJ. Pharmacology ofoxaliplatin and the use of pharmacogenomics to individualize therapy. Cancer Treat Rev. 2005;31:90–105.
• 23. DeLeve LD, Wang X, Kanel GC, Ito Y, Bethea NW, McCuskey MK, et al. Decreased hepatic nitric oxide production contributes to the development of rat sinusoidal obstruction syndrome. Hepatology. 2003;38:900–8.
• 24. Laurent A, Nicco C, Chéreau C, Goulvestre C, Alexandre J, Alves A, et al. Controlling tumour growth by modulating endogenous production of reactive oxygen species. Cancer Res. 2005;65:948–56.
• 25. Soubrane O, Brouquet A, Zalinski S, Terris B, Brézault C, Mallet V, et al. Predicting high grade lesions of sinusoidalobstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases correlation with post-hepatectomy outcome. Ann Surg. 2010;251:454–60.
• 26. Derici H, Kamer E, Unalp HR, Diniz G, Bozdag AD, Tansug T, et al. Effect of sildenafil on wound healing: an experimental study. Langenbecks Arch Surg. 2010;395:713-8.
• 27. Cakir T, Ozer I, Bostanci EB, Keklik TT, Ercin U, Bilgihan A, et al. Increased collagen maturity with sildenafil citrate: experimental high risk colonic anastomosis model. Int J Surg. 2015;13:152-6.