Study On The Antitumor Effect Of Linomide In Treatment Of Human Squamous Cell Carcinoma Of Tongue And Its Related Mechanisms

Human squamous cell carcinoma (SCC) of tongue is the most common malignant tumor in the oral and maxillofacial region. It is still a fetal disease with high recurrency and mortality. New approaches in treatment of SCC are thus urgently needed.Angiogenesis and microcircuiation establishment are necessary for the consistent growth and metastasis of solid tumors. Recently, much effort has been spent to understand the relationship between angiogenesis and progressive tumor development. In the early 70's, Folkman reported a new way to control tumor growth 梐ntiangiogenesis. If the tumor angiogenesis is inhibited effectively, the tumor cells will be killed by reducing the blood flow and nutrition provision. Many studies have suggested that the inhibition of angiogenesis should be a highly effective method in the therapy of malignant tunors.Linomide (N-phenylmethyl- 1,2 - dihydro - 4 - hydroxyl - 1- methyl -2- oxo - quinoline 3- carboxamine) with characteristics of possible value of immune modulation can increase the delayed hypersensitivity response to bacterial antigens and enhance the lymphoproliferative response to T-cell mitogens and alloantigens. It was used as immunomodulator in the treatment of autoimmune or infectious disease and transplantation patients. In the recent years, it was reported to have inhibitory effect on several solid tumors such as prostatic cancer, renal carcinoma and Lewis lung cancer. Until recently, Vokanovic reported that it was the antiangiogenesis activity that was related to its antitumor function.However, the exact mechanism of linomide is now not very clear. The objective of this study is to investigate the antitumor effect of linomide in treatment of transplanted human squamous cell carcinoma of tongue in BALB/C nude mice and its related mechanisms. The inhibitory effect of linomide on the proliferation of human umbilical vein endothelial cell was also studied using cellular and molecular biological methods. These data would be of value to clarify the antiangiogenesis effect of linomide and provide new approach in the biotherapy of malignant tumors.Section 1The antitumor effect of linomide in treatment of transplanted humansquamous cell carcinoma of tongue in nude mice and its relatedmechanismsAnimal models were established by inoculating the human squamous cell carcinoma cell line Tca8113 into the BALB/c nu/nu nude mice. The mice were randomly divided into three groups and received linomide therapy.-8-The microvessel density (MVD) in the tumor tissue after linomide therapy was investigated by immunohistochemistry methods. The expression of VEGF and VEGFR (Fltl) mRNA was detected in the tumor tissue from mice of different groups by semi-quantitative RT-PCR and serum levels of VEGF was measured by ELISA assay. The apoptotic cells in the tumor tissue after linomide therapy was determined in formalin-fixed, paraffin-embedded histological sections by TUNEL. The expressions of many oncogenes and tumor suppressor genes were detected by Genechips in the tumor tissue derived from mice treated with linomide and controls.The results showed that subcutaneous tumor growth was significantly inhibited in mice treated with linomide when compared with that in controls (p<0.01). The tumor volume in mice received linomide l00mg/kg/d i.p. decreased when compared with that in mice treated with 50mg/kg/d linomide (p<0.01). And mice treated with linomide survived longer than controls (p<0.01). The microvessel density (MVD) in tumor tissue from mice treated with linomide 100mg/kg/d, 50mg/kg/d decreased 38.2%, 57.8% respectively when compared with that in mice of control group. There was no significant difference in the expression of VEGF mRNA inside the tumor tissue between the control group and linomide therapy groups. The serum VEGF level didn't changed after linomide therapy. The expression of Flt-1 mRNA in tumor tissue was inhibited in mice treated with linomide lOOmg/kg/d, 50mg/kg/d when compared with that in controls (p<0.01). The determination of apop...