L-arginine reduces cell proliferation and ornithine decarboxylase activity in patients with colorectal adenoma and adenocarcinoma.

PURPOSE: Evidence suggests that the majority of colorectal carcinomas arise from adenomas, and L-arginine suppresses colorectal tumorigenesis. We suppose that L-arginine may inhibit the process of carcinogenesis from colorectal adenoma to adenocarcinoma. The aim of this study was to investigate the effects of L-arginine on the formation and development of colorectal tumors. EXPERIMENTAL DESIGN: We selected 60 patients with colorectal cancer and 60 patients with colorectal adenoma (CRA) and divided them into four groups of 30 patients each. We gave 30 g (120 mL) of L-arginine everyday for 3 days to the test groups, whereas L-arginine was substituted by 5% glucose in the control groups. The expression of the proliferating cell nuclear antigen, survivin, and nitric oxide synthase was examined immunohistochemically, and ornithine decarboxylase (ODC) activity was examined spectrophotometrically. Serum nitric oxide (NO) was detected by the Griess assay. RESULTS: In patients with CRA, the proliferating cell nuclear antigen and survivin labeling indexes and ODC activity of the tumor and paratumor mucosa in the L-arginine-treated group after L-arginine treatment were significantly lower as compared with the corresponding pretreatment values (P < 0.01). Moreover, inducible nitric oxide synthase expression in the tumor markedly increased after L-arginine treatment (P < 0.05). Serum NO levels in the patients with colorectal cancer were markedly higher than those in the patients with CRA, and L-arginine treatment was responsible for this increase (P < 0.05). CONCLUSIONS: Our results show that L-arginine can restrain crypt cell hyperproliferation and the expression of survivin, an inhibitor of apoptosis protein. This suggests that L-arginine can block the formation and development of colorectal tumors, and this effect might be related to the increased serum NO concentration and decreased ODC activity.

Correlation between expression of cyclooxygenase-2 and angiogenesis in human gastric adenocarcinoma.

AIM: To evaluate the expression of cyclooxygenase (COX-2) and the relationship with tumor angiogenesis and advancement in gastric adenocarcinoma. METHODS: Immunohistochemical stain was used for detecting the expression of COX-2 in 45 resected specimens of gastric adenocarcinoma; the monoclonal antibody against CD34 was used for displaying vascular endothelial cells, and microvascular density (MVD) was detected by counting of CD34-positive vascular endothelial cells. Paracancerous tissues were examined as control. RESULTS: Immunohistological staining with COX-2-specific polyclonal antibody showed cytoplasmic staining in the cancer cells, some atypical hyperplasia and intestinal metaplasia,as well as angiogenic vasculature present within the tumors and prexisting vasculature adjacent to cancer lesions. The rate of expression of COX-2 and MVD index in gastric cancers were significantly increased, compared with those in the paracancerous tissues (77.78 vs 33.33 %, 58.13+/-19.99 vs 24.02+/-10.28, P<0.01, P<0.05, respectively). In 36 gastric carcinoma specimens with lymph node metastasis, the rate of COX-2 expression and MVD were higher than those in the specimens without metostasis (86.11 vs 44.44 %, 58.60+/-18.24 vs 43.54+/-15.05, P<0.05, P<0.05, respectively). The rate of COX-2 expression and MVD in the specimens with invasive serosa were significantly higher than those in the specimens without invasion to serosa (87.88 vs 50.0 %, 57.01+/-18.79 vs 42.35+/-14.65, P<0.05, P<0.05). Moreover, MVD in COX-2-positive specimens was higher than that in COX-2-negative specimens (61.29+/-14.31 vs 45.38+/-12.42,P<0.05). COX-2 expression was positively correlated with MVD (r=0.63, P<0.05). CONCLUSION: COX-2 expression might correlate with the occurance and advancement of gastric carcinoma and is involved in tumor angiogenesis in gastric carcinoma. It is likely that COX-2 by inducing angiogenesis can be one of mechanisms which promotes invasion and metastasis of gastric carcinoma. It may become a new therapeutic target for anti-angiogenesis.

Relationship between the expression of iNOS,VEGF,tumor angiogenesis and gastric cancer.

AIM: To investigate the relationship between the expression of inducible nitric oxide synthase(iNOS),vascular endothelial growth factor(VEGF),the microvascular density (MVD) and the pathological features and clinical staging of gastric cancer. METHODS: Immunohistochemical staining was used for detecting the expression of iNOS and VEGF in 46 resected specimens of gastric carcinoma; the monoclonal antibody against CD34 was used for displaying vascular endothelial cells, and MVD was detected by counting of CD34-positive vascular endothelial cells. RESULTS: Of 46 resected specimens of gastric carcinoma,the rates of expressions of iNOS and VEGF were 58.70% and 76.09%, respectively,and MVD averaged 55.59+/-19.39.Judged by the standard TNM criteria, the rate of expression of iNOS in stage IV (84.46%) was higher than those in stage I,II, III(Fish exact probabilities test, P=0.019,0.023 and 0.033,respectively);the rates of expression of VEGF in stage III,IV (76.0%,92.31%,respectively) were higher than those in stage I,II (Fish exact probabilities test, P=0.031,0.017,0.022 and 0.019). MVDs in stage III,IV(64.72+/-14.96,67.09+/-18.29,respectively) were higher than those in stage I,II(t=2.378,4.015,2.503 and 2.450, P<0.05,P<0.001,P<0.001, P<0.05,respectively). In 37 gastric carcinoma specimens with lymph node metastasis, MVD(68.69+/-18.07) and the rates of expression of iNOS and VEGF(70.27%,83.78%,respectively) were higher than those in the specimens with absence of metastasis (t=2.205, chi(2)=6.3587, chi(2)=6.2584, P<0.01, P<0.05, P<0.05, respectively). MVD and the expressions of iNOS and VEGF were not correlated to the location,size or grade of tumor,nor with the depth of invasion of tumor; MVDs in the positive iNOS and VEGF specimens(59.88+/-18.02,58.39+/-17.73, respectively) were higher than those in the negative iNOS and VEGF specimens (chi(2)=6.3587 and 6.1574, P<0.05, P<0.05,respectively);thus the expressions of iNOS and VEGF was correlated to MVD,but the expression of iNOS was not correlated to that of VEGF. In addition,of the 46 surviving patients, the 5-year survival rate of patients with positive iNOS or VEGF tumors was significantly less than that of patients with negative iNOS-or VEGF tumors(chi(2)=4.3842 and 5.4073, P<0.05, P<0.05, respectively). CONCLUSION: The expressions of iNOS and VEGF are closely related to tumor angiogenesis,and are involved in the advancement and the lymph node metastasis; thus MVD and the expressions of iNOS and VEGF may serve indexes for evaluating staging of gastric carcinoma and forecasting its risk of metastasis, which will help establish a comprehensive therapeutical measure of post-operative patients and provide a new approach to tumor therapy.