Antitumor effects of bevacizumab in combination with fluoropyrimidine drugs on human oral squamous cell carcinoma

Abstract

Vascular endothelial growth factor (VEGF) serves an important role in new blood vessel formation or angiogenesis, which is a critical event in tumor growth and metastasis. Bevacizumab is a humanized monoclonal antibody against VEGF-A, whereas S-1 is a fluoropyrimidine antineoplastic agent that induces apoptosis in various types of cancer cells. The present study evaluated the antitumor effects of bevacizumab in combination with 5-fluorouracil (5-FU) or S-1 against oral squamous cell carcinoma (OSCC) in vitro and in vivo . Two human OSCC cell lines were used, namely the high VEGF-A-expressing HSC-2 cells and the low VEGF-A-expressing SAS cells. MTT assay was used to evaluate the effect of bevacizumab and/or 5-FU against HSC-2 and SAS cell proliferation. Additionally, the antitumor effect of bevacizumab was evaluated alone and in combination with S-1 against HSC-2 tumors in nude mice. S-1 (6.9 mg/kg/day) was administered orally every day for 3 weeks, and bevacizumab (5 ml/kg/day) was injected intraperitoneally twice per week for 3 weeks. Apoptotic cells in mouse tumors were detected using the TUNEL method, and cell proliferation and microvessel density (MVD) were determined by immunohistochemical staining of Ki-67 and CD31, respectively. Bevacizumab alone did not inhibit OSCC cell proliferation in vitro , and did not exhibit any synergistic inhibitory effect in combination with 5-FU in vitro . However, combined bevacizumab and S-1 therapy exerted synergistic and significant antitumor effects in vivo on HSC-2 tumor xenografts, and induced apoptosis in tumor cells. Furthermore, this combination therapy led to decreased MVD and cell proliferative abilities, as well as increased apoptosis in residual tumors. The present findings suggested that the bevacizumab plus S-1 combination therapy may exert antitumor effects in high VEGF-A-expressing OSCC cells.

The Correlation Between CD44 and Angiogenesis in Oral Squamous Cell Carcinoma Induced in Buccal Pouch in Syrian Hamster that Underwent Radiotherapy

“…On the other hand, It was previously reported, that positive expression of CD44 actively interacts with surrounding stromal cells in the tumor microenvironment. The tumor cells incorporate pre-existing vessels and utilize the perivascular niche for their survival (Krishnamurthy et al, 2010). in addition, Some studies observed that positive cells of CD44 are located in the perivascular niche in the models as well as in human tumor tissues.…”

“…VEGF is considered as a homodimeric glycoprotein with a molecular weight of about 45 kDa, which is the main key of angiogenesis in cancer, in which it is regulator by oncogene expression (Carmeliet, 2005). VEGF-Atargeting monoclonal antibody therapies have provided successful results in diverse types of cancer like colorectal cancer and head and neck cancer (Itashiki et al, 2021). Bevacizumab is a molecularly targeted medication with different Characteristics compared with conventional chemotherapeutic agents.…”

“…It directly binds to VEGF-A around the tumor and prevents tumor angiogenesis (Yoshida et al, 2018). Moreover, bevacizumab normalizes residual blood vessels and develops the drug delivery system into cancer so that medications reach to cancer at (Itashiki et al, 2021) .…”

Dynamics of changes in expression of VEGF neoangiogenic factor in tumor tissue bioptates in patients with squamous cell carcinoma of oral mucosa receiving cetuximab treatment and chemotherapy

“…Хотя показатели выживаемости при плоскоклеточном раке полости рта улучшились за последние два десятилетия, прогноз все еще остается неблагоприятным по сравнению с развитием терапии и успехом, достигнутым для других видов злокачественных опухолей. Прогностические факторы многочисленны, а их взаимодействия сложны и до сих пор неясны [12][13][14].…”

Characterization of the Expression of Angiogenic Factors in Cutaneous Squamous Cell Carcinoma of Domestic Cats

“…In contrast, other studies found no significant differences in VEGF-A expression in human oral SCC compared to epithelial dysplasia or normal gingiva [ 81 , 82 ]. Furthermore, treatment with the VEGF-A antagonist bevacizumab, alone or in combination with 5-fluorouracil chemotherapy, failed to inhibit human oral SCC cell proliferation in vitro [ 83 ]. With regard to PLGF, transcripts and protein levels were upregulated in human oral SCC compared to normal tissue.…”