The use of crevicular fluid to assess markers of inflammation and angiogenesis, IL-17 and VEGF, in patients with solid tumors receiving zoledronic acid and/or bevacizumab

  • Erofili PapadopoulouEmail author
  • Ourania Nicolatou-Galitis
  • Ioannis Papassotiriou
  • Helena Linardou
  • Aikaterini Karagianni
  • Konstantinos Tsixlakis
  • Anthi Tarampikou
  • Kelly Michalakakou
  • Emmanouil Vardas
  • Dimitrios Bafaloukos
Original Article



Crevicular fluid was used to assess interleukin-17 (IL-17) and vascular endothelial growth factor (VEGF) in cancer patients receiving zoledronic acid and/or bevacizumab. The markers were also assessed in the serum.


Twenty-five patients were included and comprised three groups: patients who received zoledronic acid (n = 9), patients who received bevacizumab (n = 9), and patients who received zoledronic acid combined with bevacizumab (n = 5). One patient received zoledronic acid and everolimus and another received zoledronic acid, bevacizumab, and temsirolimus. IL-17 and VEGF were measured by standard quantitative ELISA kits and assessed in two study points.


Twenty-four patients maintained good periodontal health; one had asymptomatic osteonecrosis of the jaw. First assessment: 44 samples were collected; 21 from serum and 23 from crevicular fluid. Second assessment, 6 months later: 11 samples were collected; 6 from serum and 5 from crevicular fluid. IL-17 was detected in all samples, in serum and crevicular fluid, and remained unchanged at both time points. Serum VEGF in patients with bevacizumab alone or combined with zoledronic acid was significantly lower compared with that of patients who received zoledronic acid alone. VEGF was not detected in the crevicular fluid.


Crevicular fluid might be an easy, non-invasive means to assess IL-17. The stable values of IL-17 in crevicular fluid and serum and the lack of VEGF in the crevicular fluid could be related to the good periodontal health of our patients. Further studies are needed to assess IL-17 and VEGF in the crevicular fluid in patients with and without periodontal disease.


Crevicular fluid Interleukin-17 Bevacizumab mTOR inhibitors VEGF Zoledronic acid 


Compliance with ethical standards

They were all informed about the study and signed a detailed informed consent form. Ethical approval for the study was obtained by the Committee of Research and Ethics of the Dental School, National and Kapodistrian University of Athens.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Yang B, Hang H, Fung A, Zhao H et al (2014) The role of interleukin 17 in tumour proliferation, angiogenesis and metastasis. Mediat Inflamm 2014:623759. Google Scholar
  2. 2.
    Cheng WC, Hughes FJ, Taams LS (2014) The presence, function and regulation of IL-17 and Th17 cells in periodontitis. J Clin Periodontol 41:541–549. CrossRefGoogle Scholar
  3. 3.
    Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y, Cua DJ, Takayanagi H (2006) Th17 functions as an osteoclastogenic helper T cell subject that links T cell activation and bone destruction. J Exp Med 27(203):2673–2682. CrossRefGoogle Scholar
  4. 4.
    Kirkham BW, Lassere MN, Edmonds JP, Juhasz KM, Bird BA, Lee CS, Shnier R, Portek IJ (2006) Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort). Arthritis Rheum 54:1122–1131. CrossRefGoogle Scholar
  5. 5.
    Gacche RN, Meshram RJ (2013) Targeting tumor micro-environment for design and development of novel anti-angiogenic agents arresting tumor growth. Prog Biophys Mol Biol 113:333–354. CrossRefGoogle Scholar
  6. 6.
    Bissachi D, Benelli R, Vanzetto C et al (2003) Anti-angiogenesis and angioprevention: mechanisms, problems and perspectives. Cancer Detect Prev 27:229–238CrossRefGoogle Scholar
  7. 7.
    Nicolatou-Galitis O, Razis E, Galiti D, Galitis E, Labropoulos S, Tsimpidakis A, Sgouros J, Karampeazis A, Migliorati C (2015) Periodontal disease preceding osteonecrosis of the jaw (ONJ) in cancer patients receiving aniresorptives alone or combined with targeted therapies: report of 5 cases and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol 120:699–706. CrossRefGoogle Scholar
  8. 8.
    Tsao C, Darby I, Ebeling P, Walsh K et al (2013) Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac Surg 71:1360–1366. CrossRefGoogle Scholar
  9. 9.
    Vincenzi B, Napolitano A, Zoccoli A, Iuliani M, Pantano F, Papapietro N, Denaro V, Santini D, Tonini G (2012) Serum VEGF levels as predictive marker of bisphosphonate-related osteonecrosis of the jaw. J Hematol Oncol 5:56. CrossRefGoogle Scholar
  10. 10.
    Subrahmanyaam MV, Sangyeetha M (2003) Gingival crevicular fluid a marker of the periodontal disease activity. Indian J Clin Biochem 18:5–7. CrossRefGoogle Scholar
  11. 11.
    Longo PL, Artese HPC, Horliana ACRT, Gomes GH, Ramito GA et al (2015) Inflammatory markers in gingival crevicular fluid of periodontitis patients with type 2 diabetes mellitus according to glycerine control: a pilot study. Dent Res J (Isfahan) 12:449–455CrossRefGoogle Scholar
  12. 12.
    Noonan K, Marchionni L, Anderson J, Pardoll D, Roodman GD, Borrello I (2010) A novel role of IL-17-producing lymphocytes in mediating lytic bone disease in multiple myeloma. Blood 116:3554–3563. CrossRefGoogle Scholar
  13. 13.
    Luo Z, Wang H, Chen J, Kang J, Sun Z, Wu Y (2015) Overexpression and potential regulatory role of IL-17F in pathogenesis of chronic periodontitis. Inflammation 38:978–986. CrossRefGoogle Scholar
  14. 14.
    Zenobia C, Hajishengallis G (2015) Basic biology and role of interleukin-17 in immunity and inflammation. Periodontol 69:142–159. CrossRefGoogle Scholar
  15. 15.
    Ajuz N, Antunes H, Mendonca T, Pires F et al (2014) Immunosuppression of interleukin-17 in apical periodontitis lesions. JOE 40:1400–1403. Google Scholar
  16. 16.
    Kikuiri T, Kim I, Yamaza T, Akiyama K, Zhang Q, Li Y, Chen C, Chen WJ, Wang S, le AD, Shi S (2010) Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw-like disease in mice. J Bone Miner Res 25:1668–1679. CrossRefGoogle Scholar
  17. 17.
    Zhang Q, Atsuta I, Liu S, Chen C, Shi S, Shi S, le AD (2013) IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the jaws. Clin Cancer Res 19:3176–3188. CrossRefGoogle Scholar
  18. 18.
    Rosella D, Papi P, Giardino R, Cicalini E, Piccoli L, Pompa G (2016) Medication-related osteonecrosis of the jaw: clinical and practical guidelines. J Int Soc Prev Community Dent 6:97–104. CrossRefGoogle Scholar
  19. 19.
    Nicolatou-Galitis O, Papadopoulou E, Sarri T, Boziari P, Karayianni A, Kyrtsonis MC, Repousis P, Barbounis V, Migliorati CA (2011) Osteonecrosis of the jaw in oncology patients treated with bisphosphonates: prospective experience of a dental oncology referral center. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 112:195–202. CrossRefGoogle Scholar
  20. 20.
    Dimopoulos MA, Kastritis E, Bamia C, Melakopoulos I, Gika D, Roussou M, Migkou M, Eleftherakis-Papaiakovou E, Christoulas D, Terpos E, Bamias A (2009) Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 20:117–120. CrossRefGoogle Scholar
  21. 21.
    Ripamonti CI, Maniezzo M, Campa T, Fagnoni E, Brunelli C, Saibene G, Bareggi C, Ascani L, Cislaghi E (2009) Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 20:137–145. CrossRefGoogle Scholar
  22. 22.
    Vladau M, Cimpean AM, Balica RA, Jitariu AA, Popovici RA, Raica M (2016) VEGF/VEGFR2 Axis in periodontal disease progression and angiogenesis: basic approach for a new therapeutic strategy. In Vivo 30:53–60Google Scholar
  23. 23.
    Padma R, Anaji S, Indeevar P, Indranil S, Chetan SK (2014) Vascular endothelial growth factor levels in gingival crevicular fluid before and after periodontal therapy. J Clin Diagn Res 8:75–79Google Scholar
  24. 24.
    Prapulla DV, Sujatha PB, Pradeep AR (2007) Gingival crevicular fluid VEGF levels in periodontal health and disease. J Periodontol 78:1783–1787. CrossRefGoogle Scholar
  25. 25.
    Santini D, Vincenzi B, Battistoni F et al (2007) In vivo perspective study about the effects of weekly low dose administration of zoledronic acid (ZA) on angiogenesis. J Clin Oncol 25(suppl):152Google Scholar
  26. 26.
    Santini D, Vincenzi B, Dicuonzo G, Avvisati G, Massacesi C, Battistoni F, Gavasci M, Rocci L, Tirindelli MC, Altomare V, Tocchini M, Bonsignori M, Tonini G (2003) ZA induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 9:2893–2897Google Scholar
  27. 27.
    Tas F, Duranyildiz D, Oguz H, Camlica H, Yasasever V, Topuz E (2008) Effect of zoledronic acid on serum angiogenic factors in patients with bone metastases. Med Oncol 25:346–349. CrossRefGoogle Scholar
  28. 28.
    Thumbigere-Math V, Michalowicz B, Hughes PJ, Basi DL et al (2016) Serum markers of bone turnover and angiogenesis in bisphosphonate-related osteonecrosis of the jaw patients following discontinuation of long-term intravenous bisphosphonate therapy. J Oral Maxillofac Surg 74(4):738–746. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Erofili Papadopoulou
    • 1
    Email author
  • Ourania Nicolatou-Galitis
    • 1
  • Ioannis Papassotiriou
    • 2
  • Helena Linardou
    • 3
  • Aikaterini Karagianni
    • 4
  • Konstantinos Tsixlakis
    • 4
  • Anthi Tarampikou
    • 5
  • Kelly Michalakakou
    • 2
  • Emmanouil Vardas
    • 1
  • Dimitrios Bafaloukos
    • 5
  1. 1.Clinic of Hospital Dentistry, Dental SchoolNational and Kapodistrian University of AthensAthensGreece
  2. 2.Department of Clinical Biochemistry‘Aghia Sophia’ Children’s HospitalAthensGreece
  3. 3.Oncology Unit‘Metropolitan Hospital’AthensGreece
  4. 4.Clinic of Oral Diagnosis and Radiology, Dental SchoolNational and Kapodistrian University of AthensAthensGreece
  5. 5.1st Oncology Department‘Metropolitan Hospital’PiraeusGreece

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