Antineoplastic Agents Aggravate the Damages Caused by Nicotine on the Peri-implant Bone: an in Vivo Histomorphometric and Immunohistochemical Study in Rats

Overview

Journal Clin Oral Investig

Specialty Dentistry

Date 2021 Aug 13

PMID 34386857

Authors

Juliano Milanezi de Almeida

Edilson Ervolino

David Jonathan Rodrigues Gusman

Luiz Guilherme Fiorin

Breno Edson Sendao Alves

Fernando Pozzi Semeghini Guastaldi

Henrique Rinaldi Matheus

Affiliations

Soon will be listed here.

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.

Citing Articles

Leukopenia, weight loss and oral mucositis induced by 5-Fluorouracil in hamsters' model: A regenerative approach using electrospun poly(Lactic-co-Glycolic Acid) membrane.

Chor A, Dutra H, Dias M, Goncalves R, Takiya C, Rossi A Oncotarget. 2025; 16:103-117.

PMID: 39969203 PMC: 11837862. DOI: 10.18632/oncotarget.28685.

References

Hecht S . Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer. 2003; 3(10):733-44. DOI: 10.1038/nrc1190. View

Liauw S, Connell P, Weichselbaum R . New paradigms and future challenges in radiation oncology: an update of biological targets and technology. Sci Transl Med. 2013; 5(173):173sr2. PMC: 3769139. DOI: 10.1126/scitranslmed.3005148. View

Pietras K, Hanahan D . 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. 2004; 23(5):939-52. DOI: 10.1200/JCO.2005.07.093. View

Lorch J, Goloubeva O, Haddad R, Cullen K, Sarlis N, Tishler R . 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. 2011; 12(2):153-9. PMC: 4356902. DOI: 10.1016/S1470-2045(10)70279-5. View

Vermorken J, Peyrade F, Krauss J, Mesia R, Remenar E, Gauler T . 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. 2014; 25(3):682-688. PMC: 3933250. DOI: 10.1093/annonc/mdu003. View

Longley D, Harkin D, Johnston P . 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003; 3(5):330-8. DOI: 10.1038/nrc1074. View

Cho J, Manandhar S, Lee H, Park H, Kwak M . Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance. Cancer Lett. 2007; 260(1-2):96-108. DOI: 10.1016/j.canlet.2007.10.022. View

Wang D, Lippard S . Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov. 2005; 4(4):307-20. DOI: 10.1038/nrd1691. View

van Kuilenburg A, Meinsma R, Zonnenberg B, Zoetekouw L, Baas F, Matsuda K . Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity. Clin Cancer Res. 2003; 9(12):4363-7. View

10.

Urushiyama H, Jo T, Yasunaga H, Michihata N, Matsui H, Hasegawa W . 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. 2018; 7(10):4863-4869. PMC: 6198210. DOI: 10.1002/cam4.1725. View

11.

Cox L, Africano N, Tercyak K, Taylor K . Nicotine dependence treatment for patients with cancer. Cancer. 2003; 98(3):632-44. DOI: 10.1002/cncr.11538. View

12.

Naseri R, Yaghini J, Feizi A . Levels of smoking and dental implants failure: A systematic review and meta-analysis. J Clin Periodontol. 2020; 47(4):518-528. DOI: 10.1111/jcpe.13257. View

13.

Kamer A, El-Ghorab N, Marzec N, Margarone 3rd J, Dziak R . Nicotine induced proliferation and cytokine release in osteoblastic cells. Int J Mol Med. 2005; 17(1):121-7. View

14.

Ma L, Zheng L, Sham M, Cheung L . Uncoupled angiogenesis and osteogenesis in nicotine-compromised bone healing. J Bone Miner Res. 2010; 25(6):1305-13. DOI: 10.1002/jbmr.19. View

15.

Kallala R, Barrow J, Graham S, Kanakaris N, Giannoudis P . The in vitro and in vivo effects of nicotine on bone, bone cells and fracture repair. Expert Opin Drug Saf. 2013; 12(2):209-33. DOI: 10.1517/14740338.2013.770471. View

16.

Terheyden H, Lang N, Bierbaum S, Stadlinger B . Osseointegration--communication of cells. Clin Oral Implants Res. 2011; 23(10):1127-35. DOI: 10.1111/j.1600-0501.2011.02327.x. View

17.

Al-Mahalawy H, Marei H, Abuohashish H, Alhawaj H, Alrefaee M, Al-Jandan B . Effects of cisplatin chemotherapy on the osseointegration of titanium implants. J Craniomaxillofac Surg. 2016; 44(4):337-46. DOI: 10.1016/j.jcms.2016.01.012. View

18.

Matheus H, Ervolino E, Faleiros P, Novaes V, Theodoro L, Garcia V . Cisplatin chemotherapy impairs the peri-implant bone repair around titanium implants: An in vivo study in rats. J Clin Periodontol. 2017; 45(2):241-252. DOI: 10.1111/jcpe.12824. View

19.

Dantas M, Verzola M, Sanita P, Dovigo L, Cerri P, Gabrielli M . The influence of Cisplatin-based chemotherapy on the osseointegration of dental implants: An in vivo mechanical and histometrical study. Clin Oral Implants Res. 2019; 30(7):603-616. DOI: 10.1111/clr.13445. View

20.

Sgolastra F, Petrucci A, Severino M, Gatto R, Monaco A . Smoking and the risk of peri-implantitis. A systematic review and meta-analysis. Clin Oral Implants Res. 2014; 26(4):e62-e67. DOI: 10.1111/clr.12333. View