Changes on food intake, body weight and salivary amylase synthesis in the submandibular gland of Wistar rats treated with Bevacizumab and cytostatics

Claudio Gastón Dubersarsky; Evelin Bachmeier; Catalina Melchora Francia; María Angélica Rivoira; Daniela Josefina Porta; Mabel Noemí Brunotto; Marcelo Adrián Mazzeo

doi:10.17126/joralres.2024.016

Claudio Gastón Dubersarsky Physiology Department, Faculty of Dentistry, UNC, Argentina. http://orcid.org/0009-0009-7777-6695
Evelin Bachmeier Physiology Department, Faculty of Dentistry, UNC, Argentina. http://orcid.org/0000-0001-5900-8603
Catalina Melchora Francia Pharmacology and Therapeutics “A”, Faculty of Dentistry, UNC, Argentina. http://orcid.org/0000-0003-2158-2030
María Angélica Rivoira Biochemistry and Molecular Biology. Institute of Health Sciences Research. INICSA-CONICET. Faculty of Medical Sciences. UNC. http://orcid.org/0000-0002-7316-1564
Daniela Josefina Porta Physiology Department, Faculty of Dentistry, UNC, Argentina. Institute of Health Sciences Research. INICSA-CONICET. http://orcid.org/0000-0003-4441-3723
Mabel Noemí Brunotto Cellular Biology “A”, Faculty of Dentistry, UNC, Argentina. http://orcid.org/0000-0001-8010-1079
Marcelo Adrián Mazzeo Physiology Department, Faculty of Dentistry, UNC, Argentina. http://orcid.org/0000-0002-7950-613X

DOI: https://doi.org/10.17126/joralres.2024.016

Abstract

Background: Bevacizumab together with 5-fluorouracil and oxaliplatin inhibit microvascular growth of tumor blood vessels and tumor proliferation. Few reports state the effect of these therapeutic schemes on salivary glands.
Materials and Methods: Food consumption, body weight and salivary amylase activity were assessed in the submandibular gland of rats. Adult male Wistar rats, of three months old with 350/400 grams body weight, under 12-hour light/dark cycles respectively, were divided into the following experimental groups: G1) Control group, G2) 5-Fluorouracil and leucovorin calcium treated group, G3) Bevacizumab treated group, G4) Oxaliplatin treated group, G5) Bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin calcium treated group and G6) Drug-free paired feeding treated group. Assessment of treatment effect was performed by one-way ANOVA. A value of p<0.05 was set for statistical significance.
Results: Salivary amylase activity in gland homogenate was G1: 137.9 ± 4.64, G2: 60.95±4.64, G3: 120.93 ± 4.96, G4: 26.17 ±4.64, G5: 10.77 ±4.64 and G6: 82.87 ±4.64 U/mg protein (mean ± S.D.) Amylase activity in the G1 group was higher relative to the other experimental groups p<0.0001.
Conclusions: The drugs 5-fluorouracil and oxaliplatin altered salivary amylase activity by serous granules of the submandibular gland interpreted as a mechanism of impaired acinar function. Bevacizumab administered in isolation did not alter salivary amylase activity compared to the control group. While the lower intake of the matched feeding group affected salivary amylase activity compared to the control group, the effect was significantly greater in animals treated with the oncology drugs used in the present animal model.
Keywords: Chemotherapy; Antibodies, monoclonal; Dietary intake; Body weight; Amylase; Submandibular gland.

References

1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74. doi: 10.1016/j.cell.2011.02.013. PMID: 21376230.

2. Ahmed Z, Bicknell R. Angiogenic signalling pathways. Methods Mol Biol. 2009;467:3-24. doi: 10.1007/978-1-59745-241-0_1. PMID: 19301662.

3. Garcia J, Hurwitz HI, Sandler AB, Miles D, Coleman RL, Deurloo R, Chinot OL. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat Rev. 2020;86:102017. doi: 10.1016/j.ctrv.2020.102017. Epub 2020 Mar 26. PMID: 32335505.

4. Willems E, Gerne L, George C, D’Hondt M. Adverse effects of bevacizumab in metastatic colorectal cancer : a case report and literature review. Acta Gastroenterol Belg. 2019;82(2):322-325. PMID: 31314196.

5. Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, Philip PA, Picus J, Yong WP, Horvath L, Van Hazel G, Erlichman CE, Holen KD. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol. 2010;28(21):3491-7. doi: 10.1200/JCO.2010.28.4075. Epub 2010 Jun 7. PMID: 20530271; PMCID: PMC2917213.

6. Thirion P, Michiels S, Pignon JP, Buyse M, Braud AC, Carlson RW, O’Connell M, Sargent P, Piedbois P; Meta-Analysis Group in Cancer. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol. 2004;22(18):3766-75. doi: 10.1200/JCO.2004.03.104. Erratum in: J Clin Oncol. 2005 Feb 20;23(6):1337-8. PMID: 15365073.

7. Madi A, Fisher D, Maughan TS, Colley JP, Meade AM, Maynard J, Humphreys V, Wasan H, Adams RA, Idziaszczyk S, Harris R, Kaplan RS, Cheadle JP. Pharmacogenetic analyses of 2183 patients with advanced colorectal cancer; potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy. Eur J Cancer. 2018;102:31-39. doi: 10.1016/j.ejca.2018.07.009. Epub 2018 Aug 13. PMID: 30114658.

8. García-GarcíaJA, Reding-Bernal A, López-Alvarenga JC. Cálculo del tamaño de la muestra en investigación en educación médica. Investigación en Educación Médica. 2013;2(8):217-224.

9. Gustavsson B, Carlsson G, Machover D, Petrelli N, Roth A, Schmoll HJ, Tveit KM, Gibson F. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer. 2015;14(1):1-10. doi: 10.1016/j.clcc.2014.11.002. Epub 2014 Nov 15. PMID: 25579803.

10. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237-51. doi: 10.1038/nrc3237. PMID: 22437869; PMCID: PMC3967236.

11. Kurk S, Peeters P, Stellato R, Dorresteijn B, de Jong P, Jourdan M, Creemers GJ, Erdkamp F, de Jongh F, Kint P, Simkens L, Tanis B, Tjin-A-Ton M, Van Der Velden A, Punt C, Koopman M, May A. Skeletal muscle mass loss and dose-limiting toxicities in metastatic colorectal cancer patients. J Cachexia Sarcopenia Muscle. 2019;10(4):803-813. doi: 10.1002/jcsm.12436. Epub 2019 May 15. PMID: 31094083; PMCID: PMC6711417.

12. Webb N, Fricke J, Hancock E, Trueman D, Ghosh S, Winstone J, Miners A, Shepelev J, Valle JW. The clinical and cost-effectiveness of supplemental parenteral nutrition in oncology. ESMO Open. 2020;5(3):e000709. doi: 10.1136/esmoopen-2020-000709. PMID: 32576610; PMCID: PMC7312316.

13. Li D, McCall LM, Hahn OM, Hudis CA, Cohen HJ, Muss HB, Jatoi A, Lafky JM, Ballman KV, Winer EP, Tripathy D, Schneider B, Barry W, Dickler MN, Hurria A. Identification of risk factors for toxicity in patients with hormone receptor-positive advanced breast cancer treated with bevacizumab plus letrozole: a CALGB 40503 (alliance) correlative study. Breast Cancer Res Treat. 2018;171(2):325-334. doi: 10.1007/s10549-018-4828-5. Epub 2018 May 22. PMID: 29789969; PMCID: PMC6076849.

14. Weickhardt AJ, Williams DS, Lee CK, Chionh F, Simes J, Murone C, Wilson K, Parry MM, Asadi K, Scott AM, Punt CJ, Nagtegaal ID, Price TJ, Mariadason JM, Tebbutt NC. Vascular endothelial growth factor D expression is a potential biomarker of bevacizumab benefit in colorectal cancer. Br J Cancer. 2015;113(1):37-45. doi: 10.1038/bjc.2015.209. PMID: 26125443; PMCID: PMC4647541.

15. Elting LS, Chang YC, Parelkar P, Boers-Doets CB, Michelet M, Hita G, Rouleau T, Cooksley C, Halm J, Vithala M, Bossi P, Escalante C, Brennan MT; Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Risk of oral and gastrointestinal mucosal injury among patients receiving selected targeted agents: a meta-analysis. Support Care Cancer. 2013;21(11):3243-54. doi: 10.1007/s00520-013-1821-8. Epub 2013 May 2. PMID: 23636648.

16. Sakai H, Kai Y, Takase K, Sato K, Kimura M, Tabata S, Yaegashi M, Sato F, Yomoto T, Narita M. Role of peptide YY in 5-fluorouracil-induced reduction of dietary intake. Clin Exp Pharmacol Physiol. 2016;43(8):753-9. doi: 10.1111/1440-1681.12588. PMID: 27130783.

17. Mazzeo MA. Alteraciones fisiopatológicas en saliva humana y en glándulas salivales de ratas tratadas con drogas oncológicas. [Tesis]. Facultad de Odontología. Universidad Nacional de Córdoba, Argentina, 2009.

18. Lee CS, Ryan EJ, Doherty GA. Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: the role of inflammation. World J Gastroenterol. 2014;20(14):3751-61. doi: 10.3748/wjg.v20.i14.3751. PMID: 24744571; PMCID: PMC3983434.

19. Ewens AD, Mihich E, Ehrke MJ. Fluorouracil plus leucovorin induces submandibular salivary gland enlargement in rats. Toxicol Pathol. 2005;33(4):507-15. doi: 10.1080/01926230490966265. PMID: 16036869.

20. Gavrilovic IT, Balagula Y, Rosen AC, Ramaswamy V, Dickler MN, Dunkel IJ, Lacouture ME. Characteristics of oral mucosal events related to bevacizumab treatment. Oncologist. 2012;17(2):274-8. doi: 10.1634/theoncologist.2011-0198. Epub 2012 Jan 26. PMID: 22282905; PMCID: PMC3286177.

21. Çakmak S, Nural N. Incidence of and risk factors for development of oral mucositis in outpatients undergoing cancer chemotherapy. Int J Nurs Pract. 2019;25(1):e12710. doi: 10.1111/ijn.12710. Epub 2018 Nov 21. PMID: 30461128.

22. Bettini G, Blandamura S, Saia G, Bedogni A. Bevacizumab-related osteonecrosis of the mandible is a self-limiting disease process. BMJ Case Rep. 2012;2012:bcr2012007284. doi: 10.1136/bcr-2012-007284. PMID: 23093510; PMCID: PMC4543697.

23. Bachmeier E, Migueles Goitea ME, Linares JA, Wietz FM, Jarchum S, Jarchum G, Brunotto MN, Mazzeo MA. Determinación de algunos marcadores de estrés oxidativo, funcionales e inmunológicos en saliva de pacientes sometidos a trasplante de médula ósea (TMO) [Determination of some oxidative stress, functional and immunological markers in the saliva of patients undergoing bone marrow transplantation (BMT).]. Rev Fac Cien Med Univ Nac Cordoba. 2021;78(4):384-390. doi: 10.31053/1853.0605.v78.n4.33227. PMID: 34962731; PMCID: PMC8765380.

24. Mazzeo MA, Linares JA, López MM, Gallará RV, Bachmeier E, Wietz FM, Finkelberg AB. Functional impairment in submandibular gland of rats induced by 5-fluorouracil and calcium leucovorin. Acta Odontol Latinoam. 2012;25(3):262-8. PMID: 23798072.