Anti-cancer effect of iNOS inhibitor and its correlation with angiogenesis in gastric cancer.
OBJECTIVE
To observe the anti-cancer effect of iNOS selective inhibitor (aminoguanidine, AG) and investigate the relationship between iNOS inhibitor and angiogenesis, infiltration or metastasis in MFC gastric cancer xenografts.


METHODS
Fifty athymic mice xenograft models were established by inoculating gastric cancer cell MFC subcutaneously. Twenty-four hours later, 0.9% sodium chloride solution, mitomycin, low dosage AG, high dosage AG, mitomycin and AG were administered by intraperitoneal injection respectively. Thus these mice were divided into five groups of 10 each randomly: control group, MMC group, AG(L) group, AG(H) group, MMC+AG(H) group. Two weeks later the mice were killed, and the tumor weight, inhibitory rate were evaluated. Greiss assay was used to detect the nitric oxide levels in plasma. HE and immunohistochemistry staining were used to examine microvessel density (MVD) and the expression of iNOS, VEGF, and PCNA. Apoptosis was detected by using TUNEL assay.


RESULTS
The inhibitory rates in MMC+AG(H) group and AG(H) group were 52.9% and 47.1% respectively, which is significant statistically compared with that of control group (0). In treatment groups, the cell proliferation index (PI) was lower and apoptosis index was higher than those of control group. Microvessel density, iNOS, and VEGF in MMC+ AG(H) group were 8.8+/-2.6, 2.4+/-1.1, and 2.1+/-1.4 respectively, which is significant statistically compared with those of control group (68.3+/-10.6, 11.3+/-1.3, and 10.3+/-1.6). The NO level in plasma of MMC+ AGH and AG(H) group were 12.7+/-2.1 and 12.9+/-2.0 mumol/L. Compared with that of control group (46.6+/-2.3 mumol/L), the difference is statistically significant.


CONCLUSIONS
AG has anticancer effect on gastric cancer, and it has positive synergistic effect with chemotherapeutic drugs. It may play important inhibitory roles in angiogenesis of gastric cancer. The anticancer effect of iNOS inhibitors may include inducing cell apoptosis, suppressing cell proliferation and reducing angiogenesis.
Department of General Surgery, the First Hospital, Jilin University, Changchun 130021, Jilin Province, China. wgymd@sina.com
Guang-Yi
GY
Wang
Bai
B
Ji
Xu
X
Wang
Jian-Hua
JH
Gu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D013274:Stomach Neoplasms / Q000473:pathology / Q000503:physiopathology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C004479:pimagedine