胃癌病因谈

胃癌病因谈新华胃癌是原发于胃部的一种常见的恶性肿瘤。临床主要表现为上腹胀闷不适、隐痛、胃纳减退、厌食、进行性贫血及消瘦，晚期上腹可扪及肿块，粪便潜血持续阳性等。据全国肿瘤普查资料，胃癌在我国北部及东部各省发病率最高，居所有恶性肿瘤发位之首，年死亡率达...

努力开垦胃癌病因研究的广阔园地

自从1982年幽门螺杆菌(下称Hp)分离成功以来,大量的研究证明Hp是活动性胃窦胃炎的主要病因。随着病变的进展,浅表性胃炎逐步发展为萎缩性胃炎、肠化和异型增生,形成癌前病变,在某些致癌因子的作用下渐渐发展为胃癌。另外,流行病学调查发现,胃癌高发区人群中有较高的Hp感染率,且Hp感染的年龄甚早,10岁以下儿童竟达50％以上,并证实Hp感染率100％的人群,胃癌的发生率较无Hp感染的人群高6倍。另外从现有的研究资料来看,Hp感染可引起胃上皮细胞增殖,Hp的代谢物可导致DNA损伤,这为肿瘤的发生奠定了一定的物质基础。

营养素密度在胃癌病因学研究中的应用

据《中华预防医学杂志》1995年29卷第6期报道 大连医科大学流行病学教研室李东光等为进一步深入研究膳食营养素与胃癌发病的联系,提出了营养素密度的概念,研究了膳食脂肪、蛋白质、碳水化合物、维生素A、C、E及β-胡萝卜素的营养素密度与胃癌的关系。 采用1:1病例对照设计,获得具有可靠资料的对子88对,以研究对象10年前50种摄入较多的主要食物作为重点,采用国际上应用较多的频度估计法获得信息,即由被调查者对各种食物的摄入频度及每次摄入量给出最适估计。

门静脉血K-ras和p53基因突变与胃癌骨转移的关系

目的：探讨门静脉血K-ras、053基因突变与胃癌骨转移的关系。方法：应用PCR-SSCP技术，对胃癌患者的门静脉血、外周静脉血分别进行K-ras、p53基因检测，术后随访1．2—3年，了解骨转移情况。结果：62例胃癌患者外周血和门静脉血中的p53和K-ras突变阳性率分别为8．06％、4．83％和38．71％、33．87％；其中11例发生了骨转移，有无骨转移p53和K-ras突变阳性率分别为81．82％、72．73％和19．92％和13．61％；剖腹后探查前或胃癌探查后门静脉血p53和K-ras突变阳性率分别为38．71％、33，87％和56．45％、62，90％，上述指标两组间比较，差异均有统计学意义（P〈0．05）。结论：检测门静脉血K-ras、p53基因突变对预测胃癌骨转移，判断预后有重要意义。

中国胃癌高发县鱼露的致突/致癌性研究

通过生物学短期试验和动物诱癌实验,我们研究了我国胃癌高发区福建长乐县(男性胃癌标化死亡率达113.20/10~5)鱼露的致突致癌作用。结果表明,鱼露经亚硝化后其乙酸乙酯萃取物具有明显的直接诱发S.typhimurum TA100回变、诱发V79细胞姐妹染色单体交换(SCE)和微核:诱发大肠杆菌PQ37SOS、使小牛胸腺DNA烷化的作用,并且能诱导人正常胃粘膜细胞DNA程序外合成(UDS),给新生Wistar大鼠灌胃后第四周和第十六周分别发现能诱发腺胃粘膜不典型增生(5/5)和腺胃癌(1/5);而未经亚硝化鱼露无此作用或作用很弱。进一步分析发现亚硝化鱼露中有N-亚硝酸胺(30,9-6.04μm),这类直接致灾致癌物的存在可能是亚硝化鱼露致突致癌作用的原因。长期食用鱼露可能与当地胃癌高发有关。

Gene therapy for gastric cancer:Is it promising?

Gastric cancer is one of the most common tumors worldwide. The therapeutic outcome of conventional therapies is inefficient. Thus, new therapeutic strategies are urgently needed. Gene therapy is a promising molecular alternative in the treatment of gastric cancer, including the replacement of defective tumor suppressor genes, the inactivation of oncogenes, the introduction of suicide genes, genetic immunotherapy, anti-angiogenetic gene therapy, and virotherapy. Improved molecular biological techniques and a better understanding of gastric carcinogenesis have allowed us to validate a variety of genes as molecular targets for gene therapy. This review provides an update of the new developments in cancer gene therapy, new principles, techniques, strategies and vector systems, and shows how they may be applied in the treatment of gastric cancer.

Relationship between abnormality of FHIT gene and EBV infection in gastric cancer

AIM: To examine the aberrant expression of fragile histidine triad (FHIT) gene and protein in gastric cancer, and to evaluate the role of FHIT gene and the relationship between FHIT gene and EBV infection in gastric carcinogenesis. METHODS: FHIT transcripts were detected by nested RT-PCR in 30 cases of gastric cancer and their products were sequenced.FHIT protein was detected by Western blot. EBV infection was detected by PCR method in 50 cases of gastric cancer. RESULTS: The wild type transcripts were detected in all 30 matched normal tissues of gastric cancer.Aberrant transcripts were found in 11/30 (36.7%) gastric cancerous tissues. Sequencing analysis of the aberrant fragments found an RT-PCR product missing exons 5-7 in one case of gastric cancer, and another product missing exons 4-7. Four of ten (40.0%) cases of primary gastric cancer showed absent or decreased expression of FHIT protein as compared with their matched normal tissues.EBV was detected in 5/50 (10%) gastric cancers,among which 4/5 (80%) had aberrant transcripts of FHIT gene. CONCLUSION: Loss of FHIT gene or FHIT protein plays an important role in carcinogenesis,development and progression of gastric cancer.EBV infection might influence carcinogenesis of gastric cancer by inducing the abnormality of FHIT gene.

Adenoviral gene therapy in gastric cancer: A review

Gastric cancer is one of the most common malignancies worldwide. With current therapeutic approaches the prognosis of gastric cancer is very poor, as gastric cancer accounts for the second most common cause of death in cancer related deaths. Gastric cancer like almost all other cancers has a molecular genetic basis which relies on disruption in normal cellular regulatory mechanisms regarding cell growth, apoptosis and cell division. Thus novel therapeutic approaches such as gene therapy promise to become the alternative choice of treatment in gastric cancer. In gene therapy, suicide genes, tumor suppressor genes and anti-angiogenesis genes among many others are introduced to cancer cells via vectors. Some of the vectors widely used in gene therapy are Adenoviral vectors. This review provides an update of the new developments in adenoviral cancer gene therapy including strategies for inducing apoptosis, inhibiting metastasis and targeting the cancer cells.

Helicobacter pylori infection and low serum pepsinogen I level as risk factors for gastric carcinoma

AIM: To study whether examination of CagA antibodies could increase the odds ratio for gastric cancer in a casecontrol study, and how often other serum markers of gastric cancer risk could be found in Helicobacter pylori-negative patients. METHODS: H pylori CagA and parietal cell antibodies (PCAs), and serum pepsinogen I (SPGI) levels were compared between patients with gastric cancer and controls who received endoscopic examination due to reasons other than gastrointestinal malignancy. RESULTS: The odds ratio (OR) for gastric cancer was 2.9 (95% CI 1.4-5.8) in H pylori + patients, and 2.4 (95% CI 1.2-4.9) in CagA+ patients. When results of H pylori and CagA antibodies were combined, OR increased to 5.0 (95% CI 2.5-10.0). Furthermore, if cardia cancer patients were excluded, the OR increased to 6.8 (95% CI 3.1-14.8). Among patients with a low SPGI level, the OR was 12.0 (95% CI 4.1-35.3). However, the risk was significant only in the older age group. The number of patients with low SPGI was significantly higher in H pylori -/CagA+ patients as compared to other cancer patients. CONCLUSION: Examination of both H pylori and CagA antibodies increases the OR for gastric cancer in our casecontrol study. CagA antibodies are important in detecting previous H pylori infection in advanced atrophic gastritis or cancer when spontaneous decline of H pylori antibodies occurs. SPGI may be helpful in screening elderly gastric cancer patients.

Mechanisms inactivating the gene for E-cadherin in sporadic gastric carcinomas

AIM： To study the role of CDH1/E-cadherin （E-cad） gene alteration profiles including mutation, loss of heterozygosity （LOH）, promoter polymorphism and hypermethylation in mechanisms of CDH1 inactivation in gastric carcinoma （GC）. METHODS： Specimens were collected surgically from 70 patients with GC. Allelotyping PCR and detection of LOH, denaturing high pressure liquid chromatography and DNA sequencing, restriction fragment length polymorphism analysis, methylation specific PCR, and immunohistochemical staining were used. RESULTS： Promoter polymorphism was not a major mechanism of E-cad inactivation. Only one truncating mutation was found in a diffuse type tumor （3%）. Both LOH and promoter hypermethylation were major mechanisms of E-cad inactivation, but interestingly, there was a negative association between the fraction of allelic loss （LOH） in tumors and hypermethylation of CDH1. Therefore LOH and hypermethylation were two different tumorigenic pathways involved in GC. CONCLUSION： Given the findings that somatic mutation was extremely low and the relationship between LOH and hypermethylation was inverse, any two combinations of these three factors cannot fulfill the classical two-hit hypothesis of CDH1 inactivation. Thus, other mechanisms operating at the transcriptional level or at the post-translational level might be required to induce E-cadherin inactivation.

Adenovirus-mediated FasL gene transfer into human gastric carcinoma

AIM: To evaluate the possible value of FasL in gastric cancer gene therapy by investigating the effects of FasL expression on human gastric cancer cell line. METHODS: An adenoviral vector encoding the full-length human FasL cDNA was constructed and used to infect a human gastric cancer (SGC-7901) cell line. FasL expression was confirmed by X-gal staining, flow cytometric analysis and RT-PCR. The effect of FasL on cell proliferation was determined by clonogenic assay, cytotoxicity was detected by MTT assay, and cell viability was measured by trypan blue exclusion. The therapeutic efficiency of Ad-FasL in vivo was investigated with a xenograft tumor model in nude mice. RESULTS: SGC-7901 cells infected with Ad-FasL showed increased expression of FasL, resulting in significantly decreased cell growth and colony-forming activity when compared with control adenovirus-infected cells. The cytotoxicity of anti-Fas antibody (CH-11) in gastric cancer cells was stronger than that of ActD (91±8 vs60±5,P<0.01), and the cytotoxicity of Ad-FasL was stronger than that of CH-11 (60±5 vs50±2, P<0.05). In addition, G1-phase arrest (67.75±0.39 vs 58.03±2.16, P<0.05) and apoptosis were observed in Ad-FasL-infected SGC-7901 cells, and the growth of SGC-7901 xenografts in nude mice was retarded after intra-tumoral injection with Ad-FasL (54% vs 0%,P<0.0001). CONCLUSION: Infection of human gastric carcinoma cells with Ad-FasL induces apoptosis, indicating that this target gene might be of potential value in gene therapy for gastric cancer.

Genetic instability of BRCA1 gene at locus D17S855 is related to clinicopathological behaviors of gastric cancer from Chinese population

AIM： To investigate genetic instability of gene BRCA1 at locus D17S855, and their relationship with clinicopathological characteristics of gastric cancer in Chinese population. METHODS： Microsatellite instability （MSI） and loss of heterozygosity （LOH） of gene BRCA1 at locus D17S855 were compared between 37 samples of gastric cancer and corresponding non-cancerous gastric tissue. RESULTS： MSI at locus D17S855 was positive in 7 of 37 samples of gastric cancer （18.95%）. MSI had a close relationship with TNM staging but no relation with lymph node metastasis, histological type or tumor differentiation. MSI positive frequency in TNM Ⅰ ＋ Ⅱ （31.58%, 6/19） was much higher than that in TNM Ⅲ＋ Ⅳ （5.56%, 1/18）, （P 〈 0.05）. LOH positive rate was 18.92% （7/37）. LOH had no relationship to histological type, tumor differentiation or lymph node metastasis, but LOH positive rate in TNM Ⅲ＋ Ⅳ was 33.33% （6/18）, much higher than that in TNM Ⅰ ＋ Ⅱ （ 5.26%, 1/19）, （P 〈 0.05）. BRCA1 protein was expressed in 14 of 37 samples of gastric cancer. The positive rates of BRCA1 protein in TNM Ⅰ ＋ Ⅱ and TNM Ⅲ＋ Ⅳ were 57.89% and 16.67%, respectively, （P 〈 0.05）. The positive rate of BRCA1 protein was 77.78% in high differentiation samples, 30.77% in middle differentiation and 12.50% in lower differentiation samples, （P 〈 0.05）. CONCLUSION： MSI of BRCA1 gene could be used as a molecular marker in early phases of sporadic gastric cancer in Chinese population. LOH occurs at later period of gastric cancer, therefore, it could be used as prognostic factor.

Risk factors for operative morbidity and mortality in gastric cancer patients undergoing total gastrectomy

AIM： To study the risk factors for morbidity and mortality following total gastrectomy. METHODS： We retrospectively reviewed the records of 125 consecutive patients who underwent total gastrectomy for gastric cancer at the Second Affiliated Hospital of Zhejiang University School of Medicine between January 2003 and March 2008. RESULTS： The overall morbidity rate was 20.8% （27 patients） and the mortality rate was 3.2% （4 patients）. Morbidity rates were higher in patients aged over 60 [odds ratio （OR） 4.23 （95% confidence interval （CI） 1.09 to 12.05）], with preoperative comorbidity [with vs without, OR 1.25 （95% CI 1.13 to 8.12）], when the combined resection was performed [combined resection vs total gastrectomy only, OR 2.67 （95% CI 1.58 to 5.06）]. CONCLUSION： Age, preoperative comorbidity and combined resection were with the rate of morbidity gastric cancer. independently associated after total gastrectomy for

Expression of macrophage migration inhibitory factor is associated with enhanced angiogenesis and advanced stage in gastric carcinomas

AIM: Macrophage migration inhibitory factor (MIF) was reported to inactivate p53 and play an essential role in the growth and angiogenesis of tumors that arise at sites of chronic inflammation. Gastric inflammation is a prerequisite for the development of gastric carcinoma (GC), which has recently been linked to Helicobacter pylori (H pylori) infection. This study aimed to investigate dinicopathological significance of MIF expression in GCs. METHODS: We selected 90 consecutive patients with GCs for investigation of the relation among MIF status, clinicopathological parameters, p53 expression and angiogenesis. MIF and p53 expression was assessed by immunohistochemistry as positive and negative groups. Tumor vascularity was evaluated by counting microvessel density on anti-CD34 stained sections. Expression status of MIF was correlated with determined dinicopathological data, p53 immunoreactivity and microvessel counts. RESULTS: Strong immunostainings of MIF were observed in the cytoplasm of cancerous cells in 40% (36/90) of cases but not in normal or metaplastic epithelia. There was no statistically significant correlation between MIF expression and age, gender, H pylori infection, tumor location, histological subtypes, lymph node metastasis or p53 expression. Early GC less frequently overexpressed MIF as compared to advanced GCs (4/20 vs 32/70, P= 0.04). A remarkably increased microvessel count was noted in GCs with MIF expression than those without MIF expression (55.1±30.1 vs 31.3±28.8, P= 0.0001). CONCLUSION: Our results suggest that expression of MIF may contribute to the progression and enhanced angiogenesis in a substantial portion of GCs.

Expression of some tumor associated factors in human carcinogenesis and development of gastric carcinoma

AIM: To study the effect of IGF-1/IGF-1R and gastrin/CCK-BR on carcinogenesis and development of human gastric carcinoma and to explore its mechanism and provide a credible theoretical foundation for early diagnosis and molecular therapy of gastric carcinoma.METHODS: mRNA expression levels of IGF-1/IGF-1R and gastrin/CCK-BR were assessed by RT-PCR method in gastric cancer tissues, adjacent mucosa, and tumor-free tissues from 56 patients with gastric carcinoma and normal gastric mucosae from 56 healthy controls. Tissue specimens were obtained by biopsy and confirmed by histological evaluation.RESULTS: The mRNA levels of IGF-1/IGF-1R were increased in gastric cancer tissues compared with normal tissues from healthy controls and successively increased in tumor-free tissues, adjacent mucosa, and gastric cancer tissues. The mRNA levels of gastrin/CCK-BR were increased in gastric cancer tissues compared with normal tissues from healthy controls. There was a significant difference between gastric cancer tissues and adjacent mucosa and tumor-free tissues, but the mRNA levels of gastrin were not significantly increased in adjacent mucosa and gastric cancer tissues compared with tumorfree tissues. The mRNA levels of CCK-BR were increased in gastric cancer tissues and adjacent mucosa compared with tumor-free tissues, but not significantly increased in adjacent mucosa and gastric cancer tissues compared with gastric cancer tissues.CONCLUSION: Overexpression of IGF-1/IGF-1R and gastrin/CCK-BR promotes the disorderly proliferation of gastric mucosa epithelia and it is of great significance in the carcinogenesis and development of gastric carcinoma.

Etiologic factors of gastric cardiac adenocarcinoma among men in Taiwan

AIM:To elucidate etiologic associations between Helicobacter pylori(H pylori),lifestyle,environmental factors and gastric cardiac adenocarcinoma(GCA)among men. METHODS:A hospital-based case-control study was conducted in Taiwan from 2000 to 2009.All cases were newly confirmed as primary GCA.Five controls were selected matching with age,sex,and admission date to each case.Participants were informedof potential risk factors with a structured question- naire by trained interviewers during hospitalization and provided a blood sample for the determination of H pylori infection.Odds ratio(OR)and 95%confidence interval(95%CI)were used to evaluate risk,and a multivariate conditional logistic regression model was performed. RESULTS:All participants recruited for this study were men,consisting of 41 cases and 205 controls.Results of the univariate analysis showed that significant factors associated with the etiology of GCA included H pylori(OR =2.69,95%CI=1.30-5.53),cigarette smoking(OR= 2.28,95%CI=1.05-4.96),working or exercising after meals(OR=3.26,95%CI=1.31-8.11),salted food (OR=2.51,95%CI=1.08-6.11),fresh vegetables(OR =0.28,95%CI=0.09-0.80),fruits(OR=0.19,95% CI=0.04-0.89),and rice as principal food(OR=0.53, 95%CI=0.30-0.85).Multivariate conditional logistic regression models indicated that a significantly elevated risk of contracting GCA was associated with working or exercising after meals(OR=3.18,95%CI=1.23-9.36) and H pylori infection(OR=2.93,95%CI=1.42-6.01). In contrast,the consumption of fresh vegetables(OR =0.22,95%CI=0.06-0.83),fruits(OR=0.28,95% CI=0.09-0.79)and rice as principal food(OR=0.48, 95%CI=0.24-0.93)remained as significant beneficial factor associated with GCA. CONCLUSION:Working or exercising after meals and H pylori infection increase the risk of GCA,but higher intakes of rice,fresh vegetables and fruits reduce the risk.

Gastric cancer incidence and mortality in Zhuanghe,China,between 2005 and 2010

AIM： To investigate the incidence and mortality of gastric cancer （GC） in Zhuanghe region, northeast China and the influencing factors for their changing trends.METHODS： All new cancer cases and deaths registered from 2005 to 2010 in Zhuanghe County were reviewed. The annual GC cases, constituent ratio, crude rates,age-standardized rates, their sex and age distribution and temporal trends were assessed. The method of annual percentage change （APC） was used to estimate the trends of GC.RESULTS： Altogether 2634 new cases of GC and 1722 related deaths were registered, which accounted for 21.04% and 19.13% of all cancer-related incidence and deaths, respectively. The age-standardized incidence rate steadily decreased from 57.48 in 2005 to 44.53 in 2010 per 10^5 males, and from 18.13 to 14.70 per 10s females, resulting in a APC of -5.81% for males and -2.89% for females over the entire period. The magnitude of APC in GC mortality amounted to -11.09% and -15.23%, respectively, as the agestandardized mortality rate steadily decreased from 42.08 in 2005 to 23.71 in 2010 per 10^5 males, and from 23.86 to 10.78 per 10^5 females. Females had a significantly lower incidence （a male/female ratio 2.80, P 〈 0.001） and mortality （a male/female ratio 2.30, P 〈 0.001）. In both genders, the peak incidence and mortality occurred in the 80-84 years age group. The age-standardized mortality/incidence ratio also decreased from the peak of 0.73 in 2005 to 0.53 in 2010 for males, and from 1.32 to 0.73 for females.CONCLUSION： Encouraging declines of incidence and mortality of GC were observed in Zhuanghe region between 2005 and 2010, possibly due to the economic development and efficient GC control strategies.

H pylori status and angiogenesis factors in human gastric carcinoma

AIM： To investigate H pylori expression in gastric cancer patients in relation to primary tumor angiogenic markers, such as microvessel density （MVD）, thymidine phosphorylase （TP）, vascular endothelial growth factor receptor-1 （VEGF-R1）, p53 and circulating VEGF levels. METHODS： Angiogenic markers were analyzed immunohistochemically in 56 primary gastric cancers. H pylori cytotoxin （vacA） and the cytotoxin-associated gene （cagA） amplification were evaluated using PCR assay. Serum H pylori IgG antibodies and serum/plasma circulating VEGF levels were detected in 39 and 38 patients by ELISA, respectively. RESULTS： A total of 69% of patients were positive for circulating IgG antibodies against Hpylori. cagA-positive H pylor/strains were found in 41% of gastric patients. vacA was found in 50% of patients; s1 strains were more highly expressed among vacA-positive patients. The presence of the s1 strain was significantly associated with cagA （P = 0.0001）. MVD was significantly correlated with both tumor VEGF expression （r = 0.361, P = 0.009） and serum VEGF levels （r = -0.347, P = 0.041）.Conversely, neither VEGF-R1 expression nor MVD was related to p53 expression. However, H pylori was not related to any angiogenic markers except for the plasma VEGF level （P = 0.026）. CONCLUSION： H pylori antigen is related to higher plasma VEGF levels, but not to angiogenic characteristics. It can be hypothesized that the toxic effects of H pylori on angiogenesis occurs in early preclinical disease phase or in long-lasting aggressive infections, but only when high H pylori IgG levels are persistent.

Significance of Survivin and PTEN expression in full lymph node-examined gastric cancer

AIM： To study the relationship between Survivin and PTEN expression and lymph node metastasis, depth of invasion and prognosis of gastric cancer patients in China.METHODS： Specimens of gastric cancer tissue were collected from the Affiliated Hospital of Jianghan University. All the 140 patients had complete examination data. All lymph nodes were found by the fat-clearing method. The interrupted serial 4-micron sections, routine hematoxylin and eosin staining and immunohistochemical methods were used to detect the lymph node metastases. Gastric cancer tissue microarray was performed to test the expression of Survivin and PTEN （17A） in gastric cancer by immunohistochemical method. All data were processed using X^2 test, Fisher＇s exact test, Kaplan-Meyer Log-rank method and Cox multivariate analysis （SPSS 12.0 software）.RESULTS： One hundred and eighteen specimens were used in our tissue microarray （utilization rate was 82.4%）. A total of 7580 lymph nodes were found. Metastases were found in 90 specimens and 1618 lymph nodes were detected. The positive rate of Survivin and PTEN expression was 52.5% （62/118） and 76.2% （90/118）, respectively. A highly positive correlation was found between Survivin and PTEN expression （X^2=4.17, P=0.04）. Survivin expression was positively correlated with UICC N stage （X^2=8.69, P=0.03） and histological classification （X^2=4.41, P=0.04） by X^2 tests. PTEN expression was positively correlated with depth of invasion （P=0.02） and histological classification （X^2=5.47, P=0.02）. But Survivin and PTEN expressions were not related with prognosis of gastric cancer patients. A significant correlation between lymph node metastasis and prognosis was demonstrated by Cox multivariate analysis （X^2=4.85, P=0.028）.CONCLUSION： Survivin is positively correlated with PTEN expression in gastric cancer and is a molecular marker of lymph node metastasis while PTEN expression is a molecular marker of advanced gastric cancer. UICC N stage is the most important prognostic factor of gastric cancer in China.

Effect of 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid in combination with carboplatin on gastric carcinoma growth in vivo

AIM： To investigate the effects of 2-（8-hydroxy-6- methoxy-l-oxo-lH-2-benzopyran-3-yl） propionic acid （NM-3） alone and in combination with carboplatin on tumor growth and apoptosis in mouse models of human gastric cancer constructed by subcutaneous implantation of histologically intact tumor tissue. METHODS： Human gastric cancer SGC-7901 tissues were implanted into the dorsal subcutis of nude mice. One week after tumors reached to a volume of 50-100 mm3 for around 1 wk, these mice were randomly divided into 8 groups （n = 10）. NM-3 was injected peritoneally at the dose of 10 mg/kg, 20 mg/kg or 40 mg/kg every other day for 5 wk, combined with carboplatin （5 mg/kg） every third day for 4 wk. As controls of combined treatment, another 4 groups of mice were injected with either NM-3 at 10 mg/kg, 20 mg/kg or 40 mg/kg, or with carboplatin alone （5 mg/kg）. The control mice received normal saline. Tumor weight, tumor growth inhibition （TGI）, and intratumoral microvessel density （MVD） were evaluated. Apoptosis of human gastric cancer was detected by TUNEL method and flow o/tometry analysis, respectively. RESULTS： The mean tumor volume （692.40 ± 58.43 mm3, 548.30 ± 66.02 mm3, 382.13 ± 43.52 mm3） after treatment with carboplatin combined NM-3 at the dose of 10 mg/kg, 20 mg/kg or 40 mg/kg was lower than that after treatment with either NM-3 at the dose of 10 mg/kg, 20 mg/kg or 40 mg/kg or with carboplatin alone. Compared with the normal saline group, NM-3 administered at 10 mg/kg, 20 mg/kg or 40 mg/kg significantly reduced the tumor weight in these groups （P 〈 0.05）. Carboplatin used alone at 5 mg/kg showed minimal effects. But NM-3 in combination with carboplatin had greater effects of tumor weight than either NM-3 or carboplatin alone. NM-3 alone at the dose 10 mg/kg or in combination with carboplatin had no obvious effects on body changes. Two mice died of diarrhea in each of the two groups treated with 40 mg/kg NM-3 or with 40 mg/kg NM-3 in combination with carboplatin. A significant increase in apoptosis was observed in the NM-3 treated groups, and the effect was more significant in the groups treated with carboplatin in combination with NM-3 at 10 mg/kg, 20 mg/kg and 40 mg/kg, than in the control group. The induction of apoptosis was positively associated with the dose of NM-3. NM-3 significantly reduced the neomicrovascular formation of gastric cancer. The MVD was lower in the groups treated with NM-3 or with NM-3 in combination with carboplatin than in the group treated with carboplatin or in the normal saline group （P 〈 0.05）. CONCLUSION： The results suggest that the inhibitory effect of NM-3 on gastric cancer growth is mediated through decreased angiogenesis and the increased induction of apoptosis. Furthermore, NM-3 alone at the dose of 10 mg/kg or in combination with carboplatin has no obvious effects on body changes, indicating that NM-3 in combination with carboplatin may be effective in the treatment of gastric cancer. The toxicity of NM-3 needs further studies.