Low-molecular-weight heparin (reviparin) diminishes tumor cell adhesion and invasion in vitro, and decreases intraperitoneal growth of colonadeno-carcinoma cells in rats after laparoscopy
Low-molecular-weight heparin (reviparin) diminishes tumor cell adhesion and invasion in vitro, and decreases intraperitoneal growth of colonadeno-carcinoma cells in rats after laparoscopy
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DOI：
10.1016/s0049-3848(03)00296-2
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发表时间：
2003-06-01
影响因子：
7.5
通讯作者：
Schulz, HU
中科院分区：
文献类型：
--
作者：
Pross, M;Lippert, H;Schulz, HU
背景资料：肿瘤细胞的转移、粘附和侵袭涉及一系列复杂的现象，这些现象可能受到糖胺聚糖的影响。我们研究了一种低分子量肝素，瑞肝素，对腹腔镜手术大鼠腹腔内肿瘤生长的影响。我们还研究了体外使用腺癌细胞CC 531的细胞毒性，抗粘附和抗侵袭作用的瑞肝素。研究方法：体外试验：在存在0.55、1.10和2.76 mg/ml瑞肝素的情况下，研究了1 × 10（5）CC 531腺癌细胞在涂有10 μ g/ml I型胶原或10 μ g/ml Matrigel的微量滴定板上的粘附，并与生理盐水进行了比较。在类似的测定中研究了I X 104腺癌细胞的细胞毒性。使用带有涂覆有100 μ g/cm（2）Matrigel的聚碳酸酯过滤器的Transwell双室，研究0.55、1.10和2.76 mg/ml瑞肝素对1 × 10（5）腺癌细胞/ml侵袭的影响。体内实验：将CC 531腺癌细胞（5 × 10（6）细胞/ml）腹膜内应用于中位体重为278 g的Wistar白化病Glaxo大鼠（n = 150，哈兰，德国）。将大鼠分为15组，每组10只动物，进行腹腔镜检查，并将含有0、0.5、2.0、4.0和10 mg瑞肝素/kg b.w.用于腹膜内灌洗或s.c. 21天后，对动物进行尸检，并测定肿瘤重量。结果如下：体外实验：我们发现在试验中使用的所有瑞肝素浓度对肿瘤细胞粘附和侵袭具有高度显著的抑制作用（p < 0.001）。在细胞毒性试验中，瑞肝素对细胞活力无影响。体内实验：我们发现，4.0和10.0 mg/kg b.w.，但不是0.5或2.0 mg/kg b.w.与仅接受盐水的对照相比，显著（p < 0.01）降低了肿瘤质量。这种效果在联合i. p.和s.c.后最为明显。在单独i. p.给药后，仅最高剂量10 mg/kg b.w.对肿瘤的生长有显著的抑制作用。结论：低分子量肝素、瑞肝素联合腹腔灌洗和皮下注射给药。注射，显著减少了在经历腹腔镜检查的大鼠中CC 531腺癌细胞的腹腔内肿瘤生长。这可能为接受腹腔镜癌症手术的患者提供额外的治疗选择。(C)2003爱思唯尔有限公司。保留所有权利。
Background: Metastases, adhesion and invasion of tumor cells involve a cascade of complex phenomena, which potentially can be affected by glycosaminoglycans. We studied the influence of a low-molecular-weight heparin, reviparin, on the intraabdominal tumor growth in rats undergoing laparoscopy. We also studied cytotoxicity, anti-adhesive, and anti-invasive effects of reviparin in vitro using adenocarcinoma cells CC531. Methods: In vitro assays: Adhesion of 1 x 10(5) CC531 adenocarcinoma cells onto microtiter plates coated with 10 mug/ml collagen type I or 10 mug/ml Matrigel was studied in the presence of 0.55; 1.10 and 2.76 mg/ml reviparin, and compared to saline. The cytotoxicity of I X 104 adenocarcinoma cells was studied in a similar assay. Transwell dual chambers with polycarbonate filters coated with 100 mug/cm(2) Matrigel were used to investigate the effect of 0.55; 1.10 and 2.76 mg/ml reviparin on the invasion of 1 x 10(5) adenocarcinoma cells/ml. In vivo experiments: CC531 adenocarcinoma cells (5 x 10(6) cells/ml) were intraperitoneally applied to Wistar Albino Glaxo rats (n = 150, Harlan, Germany) with a median weight of 278 g. The rats were divided into 15 groups with 10 animals in each group, underwent laparoscopy, and 1 ml saline containing 0, 0.5, 2.0, 4.0, and 10 mg reviparin per kg b.w. was introduced for intraperitoneal lavage or s.c. After 21 days the animals underwent an autopsy, and the tumor weight was determined. Results: In vitro experiments: We found a highly significant inhibition of tumor cell adhesion and invasion (p < 0.001) by all reviparin concentrations used in the assays. There was no effect of reviparin on the viability of cells in the cytoxicity assay. In vivo experiments: We found that application of 4.0 and 10.0 mg/kg b.w., but not 0.5 or 2.0 mg/kg b.w. significantly (p < 0.01) decreased the tumor mass compared to controls, receiving only saline. This effect was most pronounced after the combined i.p. and s.c. application, whereas after a sole i.p. application, only the highest dose of 10 mg/kg b.w. caused a significant inhibition of tumor growth. Conclusion: Low-molecular-weight heparin, reviparin, given in combination of i.p. lavage and s.c. injections, significantly diminishes intraabdominal tumor growth of CC531 adenocarcinoma cells in rats undergoing laparoscopy. This may offer additional therapeutic options for patients undergoing laparoscopic cancer surgery. (C) 2003 Elsevier Ltd. All rights reserved.