Skip to main content

Advertisement

Log in

Evaluation of the progression and treatment of experimental periodontitis in rats subjected to chemotherapy with 5-fluorouracil

  • Original Article
  • Published:
Supportive Care in Cancer Aims and scope Submit manuscript

Abstract

Aim

This study aimed to evaluate the progression and treatment of experimental periodontitis (EP) in rats treated with 5-fluorouracil (5-FU).

Materials and methods

One-hundred fifty rats were divided into groups: C—control, EP—EP induction, EP/scaling and root planing (SRP)—EP induction and SRP, 5-FU—systemic treatment with 5-FU, 5-FU/EP—systemic treatment with 5-FU and EP induction, and 5-FU/EP/SRP—systemic treatment with 5-FU, EP induction and SRP. Systemic treatment consisted of the administration of 80 and 40 mg/kg of 5-FU. The animals were euthanised at 7, 15 and 30 days. Histological and immunohistochemical analyses for the detection of the receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin (OPG) and tartrate-resistant acid phosphatase (TRAP) were performed at the furcation region. A histometric analysis was performed to evaluate the percentage of bone in the furcation region (PBF).

Results

In the 5-FU/EP and 5-FU/EP/SRP groups, there was less PBF, greater breakdown of periodontal tissues and increased immunostaining for RANKL compared with the EP and EP/SRP groups.

Conclusion

It can be concluded that 5-FU aggravates PE progression, impairs the host response to SRP mechanical therapy and does not seem to cause changes in the healthy periodontium.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Arias JL (2008) Novel strategies to improve the anticancer action of 5-fluorouracil by using drug delivery systems. Molecules 13(10):2340–2369

  2. Longley DB, Harkin DP, Johnston PG (2003) 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3(5):330–338

    Article  CAS  PubMed  Google Scholar 

  3. Ghoshal K, Jacob ST (1994) Specific inhibition of pre-ribosomal RNA processing in extracts from the lymphosarcoma cells treated with 5-fluorouracil. Cancer Res 54(3):632–636

    CAS  PubMed  Google Scholar 

  4. Santi DV, Hardy LW (1987) Catalytic mechanism and inhibition of tRNA (uracil-5-) methyltransferase: evidence for covalent catalysis. Biochemistry 26(26):8599–8606

  5. Patton JR (1993) Ribonucleoprotein particle assembly and modification of U2 small nuclear RNA containing 5-fluorouridine. Biochemistry 32(34):8939–8944

    Article  CAS  PubMed  Google Scholar 

  6. Aherne GW, Hardcastle A, Raynaud F, Jackman AL (1996) Immunoreactive dUMP and TTP pools as an index of thymidylate synthase inhibition; effect of tomudex (ZD1694) and a nonpolyglutamated quinazoline antifolate (CB30900) in L1210 mouse leukaemia cells. Biochem Pharmacol 51(10):1293–1301

    Article  CAS  PubMed  Google Scholar 

  7. Fuse N, Doi T, Ohtsu A, Yano T, Hamamoto Y, Minashi K, Tahara M, Muto M, Asaka M, Yoshida S (2008) Safety of irinotecan and infusional fluorouracil/leucovorin (FOLFIRI) in Japan: a retrospective review of 48 patients with metastatic colorectal cancer. Int J Clin Oncol 13(2):144–149

    Article  CAS  PubMed  Google Scholar 

  8. Zlotolow IM (1998) General consideration in prevention and treatment of oral manifestation of cancer therapies. In: Berget AP, Weissman DE (eds) Principles and practice of supportive oncology. Lippincott Raven, Philadelphia, p 237

    Google Scholar 

  9. Schenkein HA (2006) Host responses in maintaining periodontal health and determining periodontal disease. Periodontol 2000 40:77–93

  10. Darveau RP (2009) The oral microbial consortium’s interaction with the periodontal innate defense system. DNA Cell Biol 28(8):389–395

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein EB (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100(9):1995–2025

    Article  PubMed  Google Scholar 

  12. Vanhoecke B, De Ryck T, Stringer A, Van de Wiele T, Keefe D (2014) Microbiota and their role in the pathogenesis of oral mucositis. Oral Dis. doi:10.1111/odi.12224

    PubMed  Google Scholar 

  13. Ramakrishnan R, Gabrilovich DI (2013) Novel mechanism of synergistic effects of conventional chemotherapy and immune therapy of cancer. Cancer Immunol Immunother 62(3):405–410

    Article  CAS  PubMed  Google Scholar 

  14. Guchelaar HJ, Vermes I, Koopmans RP, Reutelingsperger CP, Haanen C (1998) Apoptosis- and necrosis-inducing potential of cladribine, cytarabine, cisplatin, and 5-fluorouracil in vitro: a quantitative pharmacodynamic model. Cancer Chemother Pharmacol 42(1):77–83

    Article  CAS  PubMed  Google Scholar 

  15. Tsukamoto Y, Usui M, Yamamoto G, Takagi Y, Tachikawa T, Yamamoto M, Nakamura M (2012) Role of the junctional epithelium in periodontal innate defense and homeostasis. J Periodontal Res 47(6):750–757

    Article  CAS  PubMed  Google Scholar 

  16. Djuric M, Cakic S, Hadzi-Mihailovic M, Petrovic D, Jankovic L (2010) Oral status in patients receiving 5-fluorouracil for colorectal cancer. J BUON 15(3):475–479

    CAS  PubMed  Google Scholar 

  17. Jensen SB, Mouridsen HT, Bergmann OJ, Reibel J, Brünner N, Nauntofte B (2008) Oral mucosal lesions, microbial changes, and taste disturbances induced by adjuvant chemotherapy in breast cancer patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 106(2):217–226

    Article  PubMed  Google Scholar 

  18. Mazzeo MA, Linares JA, Campos ML, Busamia BE, Dubersarsky C, Lavarda M, Jarchum G, Finkelberg AB (2009) Oral signs of intravenous chemotherapy with 5-Fluorouracil and Leucovorin calcium in colon cancer treatment. Med Oral Patol Oral Cir Bucal 14(3):E108–E113

  19. De Almeida JM, Theodoro LH, Bosco AF, Nagata MJ, Bonfante S, Garcia VG (2008) Treatment of experimental periodontal disease by photodynamic therapy in rats with diabetes. J Periodontol 79(11):2156–2165

    Article  PubMed  Google Scholar 

  20. Garcia VG, Longo M, Gualberto Júnior EC, Bosco AF, Nagata MJ, Ervolino E, Theodoro LH (2014) Effect of the concentration of phenothiazine photosensitizers in antimicrobial photodynamic therapy on bone loss and the immune inflammatory response of induced periodontitis in rats. J Periodontal Res 49(5):584–594

  21. Lopes NN, Plapler H, Chavantes MC, Lalla RV, Yoshimura EM, Alves MT (2009) Cyclooxygenase-2 and vascular endothelial growth factor expression in 5-fluorouracil-induced oral mucositis in hamsters: evaluation of two low-intensity laser protocols. Support Care Cancer 17(11):1409–1415

    Article  PubMed  Google Scholar 

  22. Fernandes LA, de Almeida JM, Theodoro LH, Bosco AF, Nagata MJ, Martins TM, Okamoto T, Garcia VG (2009) Treatment of experimental periodontal disease by photodynamic therapy in immunosuppressed rats. J Clin Periodontol 36(3):219–228

    Article  CAS  PubMed  Google Scholar 

  23. Feldman BF, Zinkl JG, Jain NC (2000) Schalm’s veterinary hematology, 5th edn. Lippincott Williams & Wilkins, Philadelphia, p 1344

    Google Scholar 

  24. Branda RF, Chen Z, Brooks EM, Naud SJ, Trainer TD, McCormack JJ (2002) Diet modulates the toxicity of cancer chemotherapy in rats. J Lab Clin Med 140(5):358–368

  25. Eisold S, Dihlmann S, Linnebacher M, Ryschich E, Aulmann M, Schmidt J, Schlehofer JR, Ridder R, von Knebel Doeberitz M (2002) Prevention of chemotherapy-related toxic side effects by infection with adeno-associated virus type 2. Int J Cancer 100(5):606–614

  26. Mizoguchi T, Muto A, Udagawa N, Arai, Yamashita T, Hosoya A, Ninomiya T, Nakamura H, Yamamoto Y, Kinugawa S, Nakamura M, Nakamichi Y, Kobayashi Y, Nagasawa S, Oda K, Tanaka H, Tagaya M, Penninger JM, Ito M, Takahashi N (2009) Identification of cell cycle-arrested quiescent osteoclast precursors in vivo. J Cell Biol 184(4):541–554

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Nualart Grollmus ZC, Morales Chávez MC, Silvestre Donat FJ (2007) Periodontal disease associated to systemic genetic disorders. Med Oral Patol Oral Cir Bucal 12(3):E211–E215

    PubMed  Google Scholar 

  28. Sallay K, Sanavi F, Ring I, Pham P, Behling UH, Nowotny A (1982) Alveolar bone destruction in the immunosuppressed rat. J Periodontal Res 17(3):263–274

    Article  CAS  PubMed  Google Scholar 

  29. Samejima Y, Ebisu S, Okada H (1990) Effect of infection with Eikenella corrodens on the progression of ligature-induced periodontitis in rats. J Periodontal Res 25(5):308–315

    Article  CAS  PubMed  Google Scholar 

  30. Sanavi F, Listgarten MA, Boyd F, Sallay K, Nowotny A (1985) The colonization and establishment of invading bacteria in periodontium of ligature-treated immunosuppressed rats. J Periodontol 56(5):273–280

    Article  CAS  PubMed  Google Scholar 

  31. Naidu MU, Ramana GV, Rani PU, Mohan IK, Suman A, Roy P (2004) Chemotherapy-induced and/or radiation therapy-induced oral mucositis—complicating the treatment of cancer. Neoplasia 6(5):423–431

    Article  PubMed Central  PubMed  Google Scholar 

  32. Trouvin AP, Goëb V (2010) Receptor activator of nuclear factor-κB ligand and osteoprotegerin: maintaining the balance to prevent bone loss. Clin Interv Aging 5:345–354

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Belibasakis GN, Bostanci N (2012) The RANKL-OPG system in clinical periodontology. J Clin Periodontol 39(3):239–248

    Article  CAS  PubMed  Google Scholar 

  34. Xian CJ, Cool JC, Pyragius T, Foster BK (2006) Damage and recovery of the bone growth mechanism in young rats following 5-fluorouracil acute chemotherapy. J Cell Biochem 99(6):1688–1704

    Article  CAS  PubMed  Google Scholar 

  35. Raghu Nadhanan R, Abimosleh SM, Su YW, Scherer MA, Howarth GS, Xian CJ (2012) Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss. Am J Physiol Endocrinol Metab 302(11):E1440–E1449

    Article  PubMed  Google Scholar 

  36. Ogawa K, Ueno T, Kato K, Nishitani H, Akiyoshi K, Iwasa S, Nakajima TE, Hamaguchi T, Yamada Y, Hosokawa A, Sugiyama T, Shimada Y (2013) A retrospective analysis of periodontitis during bevacizumab treatment in metastatic colorectal cancer patients. Int J Clin Oncol 18(6):1020–1024

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the Brazilian Federal Agency for the Support and Evaluation of Graduate Education (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—CAPES) for the scholarship and the São Paulo State Research Foundation (Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP) for the assistance in the development of this research (FAPESP 2011/03021-3).

Conflict of interest

The authors declare that they have no conflict of interests.

Source of funding

The present study was conducted in the Periodontics Division (Department of Surgery and Integrated Clinic of Araçatuba Dental School—UNESP) supported by São Paulo State Research Foundation (Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP 2011/03021-3).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Valdir Gouveia Garcia.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig. A1

(a): Graph showing the total number of leukocytes in the blood in each experimental group on the day of ligature placement (day -7) and 7 days later (day 0). (b): Graph showing the number of neutrophils in the blood in each experimental group on the day of ligature placement (day -7) and 7 days later (day 0). Day 0 corresponds to the day when the ligature was removed and is the day from which the periods of euthanasia (7, 15 and 30 days) were established. Symbols: §, difference in the numbers of total leukocytes and neutrophils (p < 0.05) between the day of ligature placement (day -7) and 7 days later (day 0). Statistical test: Student’s t-test. (GIF 91 kb)

(TIFF 13,951 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garcia, V.G., Novaes, V.C.N., de Almeida, J.M. et al. Evaluation of the progression and treatment of experimental periodontitis in rats subjected to chemotherapy with 5-fluorouracil. Support Care Cancer 23, 2007–2017 (2015). https://doi.org/10.1007/s00520-014-2563-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00520-014-2563-y

Keywords

Navigation