关键词: 食管肿瘤, 乙酰肝素酶, PI_88, 裸鼠

Abstract: BACKGROUND AND AIM: Heparanase (Hpa) is a kind of endo_D_glucuronidase that degrades heparin sulfate proteoglycans. It played important roles in malignant tumor's invasion and metastasis. Both phosphomannopentaosesulfate (PI_88) and antisense oligodeoxynucleotide (ASODN) are Hpa inhibitors. This study was designed to observe inhibitory effects of PI_88 and Hpa ASODN on growth and angiogenesis of esophageal squamous cell carcinoma(ESCC) xenograft tumor in nude mice. MATERIALS AND METHODS: ESCC cell line TE_13 was injected subcutaneously in nude mice to establish the ESCC subcutaneous invasive model. The nude mice were randomized into 30 mg/kg PI_88 group, 2 mg/kg Hpa ASODN group, 20 mg/kg PI_88 and 1 mg/kg ASODN combined group and sterile saline control group. Each group contained 5 mice. Tumor volume and micro vessel density (MVD) were evaluated. Hpa expression was detected by RT_PCR and immunohistochemistry. RESULTS: On the 6th day after injection, all mice had palpable tumors. On the 21st day after injection, the tumor volume was significantly smaller in ASODN group, PI_88 group and combined group than in control group(P<0.01). The tumor volume in the combined group were less than in PI_88 alone and ASODN alone groups (P<0.01), and there was no difference between the latter two groups(P>0.05). The raitio of suppression in each group was 49.67％ (ASODN), 51.44％ (PI_88) and 83.00％ (combined group). The MVD was significantly less in ASODN, PI_88 and combined group than in control group(P<0.01). The MVD in PI_88 and combined group were less than in ASODN group(P<0.01), and there was no difference between PI_88 and combined group(P>0.05). Hpa gene expression in ASODN group was 0.45±0.12, PI_88 group 1.22±0.01, combined group 0.52±0.05, control group 1.33±0.05. Hpa protein expression in ASODN group was 43.40±7.80, PI_88 group 114.40±14.47, combined group 37.40±7.20, control group 121.20±11.90. Hpa gene and protein in ASODN and combined groups was less than in control group (Hpa gene: P<0.01, Hpa protein: P<0.01). But the expression of PI_88 group showed no difference compared with control group (P>0.05), and similarly between the ASODN and combined groups(P>0.05). CONCLUSION: Administratoring ASODN and PI_88 alone or in combination could all reduce the tumor growth. PI_88 could reduce the growth of tumor and angiogenesis, but had no effects on Hpa expression in vivo. Hpa ASODN could effectively reduce the expression of heparanase to slow down the growth of xenograft and angiogenesis. Combining the two showed synergistic effect, resulting in a much better result.

Key words: esophageal neoplasms, heparanase, PI_88, nude mice