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Antineoplastic agents aggravate the damages caused by nicotine on the peri-implant bone: an in vivo histomorphometric and immunohistochemical study in rats

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Abstract

Objective

To assess the interaction between chemotherapy and normal tissues is critical to assure quality of life during and after the treatment of cancer. This study evaluated the influence of cisplatin (CIS) and 5-fluorouracil (5-FU) over the peri-implant tissues around osseointegrated titanium implants in animals previously exposed to nicotine. Materials and methods

One hundred twenty male rats were divided into two groups, receiving via subcutaneous injection, either physiological saline solution (PSS) (n = 30) or nicotine hemissulfate (NIC) (n = 90) for 30 days prior to implants’ placement. One titanium implant (4.0 × 2.2 mm) was installed in each tibia of all animals. PSS and NIC were continued for 30 days after surgery. Five days after cessation, rats were subdivided into three subgroups in accordance with systemic treatments with either PSS, CIS, or 5-FU. Euthanasia was performed at 50, 65, and 95 days post-surgery. Histometric, histopathological, and immunohistochemical analyses were performed.

Results

NIC-CIS and NIC-5FU presented lower BIC (50, 65, and 95 days) and bone area fraction occupancy (BAFO) (65 and 95 days) than group NIC. Intense inflammatory infiltration, severe tissue breakdown, reduced expression of bone formation biomarkers, and upregulation of TRAP were observed in NIC-CIS and NIC-5FU when compared with group NIC. TRAP expression was significantly higher in NIC-5FU as compared with NIC-CIS at 50 and 95 days. Groups NIC, NIC-CIS, and NIC-5FU presented statistically significant negative impact in all outcome parameters than group PSS.

Conclusion

CIS and 5-FU severely disrupted the peri-implant tissues around osseointegrated implants in animals previously exposed to nicotine.

Clinical relevance

Assessing the interaction between chemotherapy and normal tissues is critical to assure quality of life during and after the cancer treatment.

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References

  1. Hecht SS (2003) Tobacco carcinogens, their biomarkers and tobacco-induced cancer [published correction appears in Nat Rev Cancer. 2004;4:84]. Nat Rev Cancer 3:733–744. https://doi.org/10.1038/nrc1190

    Article  PubMed  Google Scholar 

  2. Phillips DH (2002) The formation of DNA adducts. In: Allison MR (ed) The Cancer Handbook. London, Macmillan, pp 293–306

    Google Scholar 

  3. Liauw SL, Connell PP, Weichselbaum RR (2013) New paradigms and future challenges in radiation oncology: an update of biological targets and technology. Sci Transl Med 5:173sr2. https://doi.org/10.1126/scitranslmed.3005148

    Article  PubMed  PubMed Central  Google Scholar 

  4. Pietras K, Hanahan D (2005) A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23:939–952. https://doi.org/10.1200/JCO.2005.07.093

    Article  PubMed  Google Scholar 

  5. Lorch JH, Goloubeva O, Haddad RI et al (2011) Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 12:153–159. https://doi.org/10.1016/S1470-2045(10)70279-5

    Article  PubMed  PubMed Central  Google Scholar 

  6. Vermorken JB, Peyrade F, Krauss J et al (2014) Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part). Ann Oncol 25:682–688. https://doi.org/10.1093/annonc/mdu003

    Article  PubMed  PubMed Central  Google Scholar 

  7. Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338. https://doi.org/10.1038/nrc1074

    Article  PubMed  Google Scholar 

  8. Cho JM, Manandhar S, Lee HR, Park HM, Kwak MK (2008) Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance. Cancer Lett 260:96–108. https://doi.org/10.1016/j.canlet.2007.10.022

    Article  PubMed  Google Scholar 

  9. Wang D, Lippard SJ (2005) Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 4:307–320. https://doi.org/10.1038/nrd1691

    Article  PubMed  Google Scholar 

  10. van Kuilenburg AB, Meinsma R, Zonnenberg BA et al (2003) Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity. Clin Cancer Res 9:4363–4367

    PubMed  Google Scholar 

  11. Urushiyama H, Jo T, Yasunaga H et al (2018) Oral fluorouracil vs vinorelbine plus cisplatin as adjuvant chemotherapy for stage II-IIIA non-small cell lung cancer: Propensity score-matched and instrumental variable analyses. Cancer Med 7:4863–4869. https://doi.org/10.1002/cam4.1725

    Article  PubMed  PubMed Central  Google Scholar 

  12. Cox LS, Africano NL, Tercyak KP, Taylor KL (2003) Nicotine dependence treatment for patients with cancer. Cancer 98:632–644. https://doi.org/10.1002/cncr.11538

    Article  PubMed  Google Scholar 

  13. Naseri R, Yaghini J, Feizi A (2020) Levels of smoking and dental implants failure: a systematic review and meta-analysis. J Clin Periodontol 47:518–528. https://doi.org/10.1111/jcpe.13257

    Article  PubMed  Google Scholar 

  14. Javed F, Rahman I (2000) Romanos GE (2009) Tobacco-product usage as a risk factor for dental implants. Periodontol 81:48–56. https://doi.org/10.1111/prd.12282

    Article  Google Scholar 

  15. Kamer AR, El-Ghorab N, Marzec N, Margarone JE 3rd, Dziak R (2006) Nicotine induced proliferation and cytokine release in osteoblastic cells. Int J Mol Med 17:121–127

    PubMed  Google Scholar 

  16. Ma L, Zheng LW, Sham MH, Cheung LK (2010) Uncoupled angiogenesis and osteogenesis in nicotine-compromised bone healing. J Bone Miner Res 25:1305–1313. https://doi.org/10.1002/jbmr.19

    Article  PubMed  Google Scholar 

  17. Kallala R, Barrow J, Graham SM, Kanakaris N, Giannoudis PV (2013) The in vitro and in vivo effects of nicotine on bone, bone cells and fracture repair. Expert Opin Drug Saf 12:209–233. https://doi.org/10.1517/14740338.2013.770471

    Article  PubMed  Google Scholar 

  18. Terheyden H, Lang NP, Bierbaum S, Stadlinger B (2012) Osseointegration–communication of cells. Clin Oral Implants Res 23:1127–1135. https://doi.org/10.1111/j.1600-0501.2011.02327.x

    Article  PubMed  Google Scholar 

  19. Al-Mahalawy H, Marei HF, Abuohashish H, Alhawaj H, Alrefaee M, Al-Jandan B (2016) Effects of cisplatin chemotherapy on the osseointegration of titanium implants. J Craniomaxillofac Surg 44:337–346. https://doi.org/10.1016/j.jcms.2016.01.012

    Article  PubMed  Google Scholar 

  20. Matheus HR, Ervolino E, Faleiros PL et al (2018) Cisplatin chemotherapy impairs the peri-implant bone repair around titanium implants: an in vivo study in rats. J Clin Periodontol 45:241–252. https://doi.org/10.1111/jcpe.12824

    Article  PubMed  Google Scholar 

  21. Dantas MVM, Verzola MHA, Sanitá PV, Dovigo LN, Cerri PS, Gabrielli MAC (2019) The influence of cisplatin-based chemotherapy on the osseointegration of dental implants: An in vivo mechanical and histometrical study. Clin Oral Implants Res 30:603–616. https://doi.org/10.1111/clr.13445

    Article  PubMed  Google Scholar 

  22. Sgolastra F, Petrucci A, Severino M, Gatto R, Monaco A (2015) Smoking and the risk of peri-implantitis. A systematic review and meta-analysis. Clin Oral Implants Res 26:e62–e67. https://doi.org/10.1111/clr.12333

    Article  PubMed  Google Scholar 

  23. https://www.euro.who.int/__data/assets/pdf_file/0009/402777/Tobacco-Trends-Report-ENG-WEB.pdf

  24. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8(6):e1000412. https://doi.org/10.1371/journal.pbio.1000412

    Article  PubMed  PubMed Central  Google Scholar 

  25. Okamoto M, Kita T, Okuda H, Tanaka T, Nakashima T (1994) Effects of aging on acute toxicity of nicotine in rats. Pharmacol Toxicol 75(1):1–6. https://doi.org/10.1111/j.1600-0773.1994.tb00316.x

    Article  PubMed  Google Scholar 

  26. Food and Drug Administration (2014). Dose calculator: conversion chemotherapy of human to animals. Retrieved from http://www.fda.gov

  27. Bois DU, Du D, Bois EF (1989) A formula to estimate the approximate surface area if height and weight be known 1916. Nutrition 5(5):303–313

    PubMed  Google Scholar 

  28. Gusman DJR, Ervolino E, Theodoro LH et al (2019) Antineoplastic agents exacerbate periodontal inflammation and aggravate experimental periodontitis. J Clin Periodontol 46(4):457–469. https://doi.org/10.1111/jcpe.13101

    Article  PubMed  Google Scholar 

  29. Campos JH, Gomes HC (2008) dos-Santos WL, Cardeal M, Ferreira LM (2008) Effect of nicotine treatment and withdrawal on random-pattern skin flaps in rats. Exp Toxicol Pathol 60(6):449–452. https://doi.org/10.1016/j.etp.2008.02.004

    Article  PubMed  Google Scholar 

  30. Matheus HR, Ervolino E, Gusman DJR et al (2020) Association of hyaluronic acid with a deproteinized bovine graft improves bone repair and increases bone formation in critical-size bone defects. J Periodontol Advance online publication. https://doi.org/10.1002/JPER.20-0613

    Article  Google Scholar 

  31. Mouraret S, Hunter DJ, Bardet C et al (2014) Improving oral implant osseointegration in a murine model via Wnt signal amplification. J Clin Periodontol 41:172–180. https://doi.org/10.1111/jcpe.12187

    Article  PubMed  Google Scholar 

  32. Thoma DS, Martin IS, Mühlemann S, Jung RE (2012) Systematic review of pre-clinical models assessing implant integration in locally compromised sites and/or systemically compromised animals. J Clin Periodontol 39(Suppl 12):37–62. https://doi.org/10.1111/j.1600-051X.2011.01833.x

    Article  PubMed  Google Scholar 

  33. Berley J, Yamano S, Sukotjo C (2010) The effect of systemic nicotine on osseointegration of titanium implants in the rat femur. J Oral Implantol 36(3):185–193. https://doi.org/10.1563/AAID-JOI-D-09-00050

    Article  PubMed  Google Scholar 

  34. Florou AN, Gkiozos IC, Tsagouli SK, Souliotis KN, Syrigos KN (2014) Clinical significance of smoking cessation in subjects with cancer: a 30-year review. Respir Care 59:1924–1936. https://doi.org/10.4187/respcare.02559

    Article  PubMed  Google Scholar 

  35. O’Malley M, King AN, Conte M, Ellingrod VL, Ramnath N (2014) Effects of cigarette smoking on metabolism and effectiveness of systemic therapy for lung cancer. J Thorac Oncol 9:917–926. https://doi.org/10.1097/JTO.0000000000000191

    Article  PubMed  Google Scholar 

  36. Petros WP, Younis IR, Ford JN, Weed SA (2012) Effects of tobacco smoking and nicotine on cancer treatment. Pharmacotherapy 32:920–931. https://doi.org/10.1002/j.1875-9114.2012.01117

    Article  PubMed  Google Scholar 

  37. Parsons A, Daley A, Begh R, Aveyard P (2010) Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis. BMJ 340:b5569. https://doi.org/10.1136/bmj.b5569

    Article  PubMed  PubMed Central  Google Scholar 

  38. Loi F, Córdova LA, Pajarinen J, Lin TH, Yao Z, Goodman SB (2016) Inflammation, fracture and bone repair. Bone 86:119–130. https://doi.org/10.1016/j.bone.2016.02.020

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lin TH, Tamaki Y, Pajarinen J et al (2014) Chronic inflammation in biomaterial-induced periprosthetic osteolysis: NF-κB as a therapeutic target. Acta Biomater 10:1–10. https://doi.org/10.1016/j.actbio.2013.09.034

    Article  PubMed  Google Scholar 

  40. Komori T (2010) Regulation of bone development and extracellular matrix protein genes by RUNX2. Cell Tissue Res 339:189–195. https://doi.org/10.1007/s00441-009-0832-8

    Article  PubMed  Google Scholar 

  41. Ivaska KK, Hentunen TA, Vääräniemi J, Ylipahkala H, Pettersson K, Väänänen HK (2004) Release of intact and fragmented osteocalcin molecules from bone matrix during bone resorption in vitro. J Biol Chem 279:18361–18369. https://doi.org/10.1074/jbc.M314324200

    Article  PubMed  Google Scholar 

  42. Martin T, Gooi JH, Sims NA (2009) Molecular mechanisms in coupling of bone formation to resorption. Crit Rev Eukaryot Gene Expr 19:73–88. https://doi.org/10.1615/critreveukargeneexpr.v19.i1.40

    Article  PubMed  Google Scholar 

  43. Stine KC, Wahl EC, Liu L et al (2014) Cisplatin inhibits bone healing during distraction osteogenesis. J Orthop Res 32:464–470. https://doi.org/10.1002/jor.22527

    Article  PubMed  Google Scholar 

  44. Morcuende JA, Gomez P, Stack J et al (2004) Effect of chemotherapy on segmental bone healing enhanced by rhBMP-2. Iowa Orthop J 24:36–42

    PubMed  PubMed Central  Google Scholar 

  45. Xian CJ, Howarth GS, Cool JC, Foster BK (2004) Effects of acute 5-fluorouracil chemotherapy and insulin-like growth factor-I pretreatment on growth plate cartilage and metaphyseal bone in rats. Bone 35:739–749. https://doi.org/10.1016/j.bone.2004.04.027

    Article  PubMed  Google Scholar 

  46. 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 99:1688–1704. https://doi.org/10.1002/jcb.20889

    Article  PubMed  Google Scholar 

  47. 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:E1440–E1449. https://doi.org/10.1152/ajpendo.00587.2011

    Article  PubMed  Google Scholar 

  48. Henemyre CL, Scales DK, Hokett SD et al (2003) Nicotine stimulates osteoclast resorption in a porcine marrow cell model. J Periodontol 74(10):1440–1446. https://doi.org/10.1902/jop.2003.74.10.1440

    Article  PubMed  Google Scholar 

  49. Warner JT, Evans WD, Webb DK, Bell W, Gregory JW (1999) Relative osteopenia after treatment for acute lymphoblastic leukemia. Pediatr Res 45:544–551. https://doi.org/10.1203/00006450-199904010-00014

    Article  PubMed  Google Scholar 

  50. Banfi A, Podestà M, Fazzuoli L et al (2001) High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia. Cancer 92:2419. https://doi.org/10.1002/1097-0142(20011101)92:9%3c2419::aid-cncr1591%3e3.0.co;2-k

    Article  PubMed  Google Scholar 

  51. Sikora M, Baranowska-Bosiacka I, Rębacz-Maron E, Olszowski T, Chlubek D (2019) The influence of the place of residence, smoking and alcohol consumption on bone mineral content in the facial skeleton. J Trace Elem Med Biol 51:115–122. https://doi.org/10.1016/j.jtemb.2018.10.012

    Article  PubMed  Google Scholar 

  52. Cunningham RS, Bell R (2000) Nutrition in cancer: an overview. Semin Oncol Nurs 16:90–98. https://doi.org/10.1053/on.2000.7141

    Article  PubMed  Google Scholar 

  53. Cortellini S, Favril C, De Nutte M, Teughels W, Quirynen M (2019) Patient compliance as a risk factor for the outcome of implant treatment. Periodontol 2000 81(1):209–225. https://doi.org/10.1111/prd.12293

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge the Department of Diagnosis and Surgery—Division of Periodontics, São Paulo State University (UNESP), School of Dentistry, Araçatuba, São Paulo, Brazil. Dr. Henrique Rinaldi Matheus received master’s degree scholarship from the São Paulo State Foundation for Research (FAPESP) (#2017/11805-0). Also, professor Juliano Milanezi de Almeida received a grant from FAPESP (#2014/11427-8). The authors thank DSP Biomedical® (Campo Largo, Parana, Brazil) for supplying the titanium implants used in this research.

Funding

Dr. Henrique Rinaldi Matheus received master’s degree scholarship from the São Paulo State Foundation for Research (FAPESP) (#2017/11805–0). Also, Professor Juliano Milanezi de Almeida received grant from FAPESP (#2014/11427–8).

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Authors and Affiliations

  1. Department of Diagnosis and Surgery–Periodontics Division, School of Dentistry, São Paulo State University (Unesp), St. José Bonifácio 1193, Vila Mendonça, Araçatuba, SP, 16015-050, Brazil

    Juliano Milanezi de Almeida, David Jonathan Rodrigues Gusman, Luiz Guilherme Fiorin, Breno Edson Sendão Alves & Henrique Rinaldi Matheus

  2. Nucleus of Study and Research in Periodontics and Implantology (NEPPI), School of Dentistry, São Paulo State University (Unesp), Araçatuba, SP, Brazil

    Juliano Milanezi de Almeida, Edilson Ervolino, David Jonathan Rodrigues Gusman, Luiz Guilherme Fiorin, Breno Edson Sendão Alves & Henrique Rinaldi Matheus

  3. Department of Basic Science, School of Dentistry, São Paulo State University (Unesp), Araçatuba, SP, Brazil

    Edilson Ervolino

  4. Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Harvard School of Dental Medicine, MA, Boston, USA

    Fernando Pozzi Semeghini Guastaldi

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  1. Juliano Milanezi de Almeida
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  2. Edilson Ervolino
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  3. David Jonathan Rodrigues Gusman
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Contributions

Juliano Milanezi de Almeida: conceptualized and acquired founding for the experiment, supervised data collection, analysis and validation, discussed the data and critically revised the manuscript. David Jonathan Rodrigues Gusman, Luiz Guilherme Fiorin, and Breno Edson Sendão Alves: involved in the execution of the experimental protocol, collected and discussed the data, and drafted the manuscript. Edilson Ervolino and Fernando Pozzi Semeghini Guastaldi were involved in the conceptualization, analyzed, validated and discussed the data, and critically revised the manuscript. Henrique Rinaldi Matheus conceptualized and acquired founding for the experiment, collected, analyzed and discussed the data, and drafted the manuscript. The final version of the manuscript was approved by all authors.

Corresponding author

Correspondence to Juliano Milanezi de Almeida.

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Ethical approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. The experimental protocol was approved by the Ethics Committee on Animal Use under protocol 595–2017 of São Paulo State University (UNESP, School of Dentistry, Araçatuba), and conducted in accordance with the ARRIVE guidelines.

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The authors declare no competing interests.

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de Almeida, J.M., Ervolino, E., Gusman, D.J.R. et al. Antineoplastic agents aggravate the damages caused by nicotine on the peri-implant bone: an in vivo histomorphometric and immunohistochemical study in rats. Clin Oral Invest 26, 1477–1489 (2022). https://doi.org/10.1007/s00784-021-04121-1

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