肝动脉输注地塞米松可抑制结直肠癌肝转移：一种局部抗血管生成疗法。

Hepatic artery dexamethasone infusion inhibits colorectal hepatic metastases: a regional antiangiogenic therapy.

作者信息

Arisawa Y, Sutanto-Ward E, Fortunato L, Sigurdson E R

机构信息

Department of Surgery, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

出版信息

Ann Surg Oncol. 1995 Mar;2(2):114-20. doi: 10.1007/BF02303625.

DOI:10.1007/BF02303625

PMID:7537164

Abstract

BACKGROUND

A randomized trial treating colorectal hepatic metastases demonstrated that hepatic arterial floxuridine (FUdR) with dexamethasone increased tumor response compared with hepatic arterial FUdR alone (Cancer 1992;69:327-34). The mechanism of this improvement is unclear.

METHODS

We investigated the effect of hepatic arterial dexamethasone with or without FUdR on the growth of colorectal hepatic metastases in an animal model. BD-IX rats were inoculated intrasplenically with 10(7) K12/TRb colon cancer cells on day 0. On day 14, the hepatic metastases were counted and hepatic arterial catheters placed for chemotherapy. Forty-eight animals were randomized to 4 groups for 14 days of infusion with heparinized saline alone (group A), heparinized saline with dexamethasone 0.03 mg/kg/d (group B), heparinized saline with FUdR 2 mg/kg/d (group C), or heparinized saline with dexamethasone 0.03 mg/kg/d plus FUdR 2 mg/kg/d (group D). The hepatic metastases were recounted by laparotomy on day 28. Response in each rat was expressed in terms of percentage change in number of hepatic nodules between the number of hepatic nodules seen on days 14 and 28. In vitro chemosensitivity of K12/TRb to dexamethasone with or without FUdR was examined using an MTT (3-(4,5-dimethylthiazole-2-yl-2,5-diphenyltetrazolium bromide; Sigma, St. Louis, MO, U.S.A.) assay. The effect of dexamethasone on tumor-induced angiogenesis was tested using an in vivo assay.

RESULTS

The mean percentage change in tumor nodules was +129% in group A, +17% in group B, -4% in group C, and -29% in group D (p = 0.002 A vs. B, p = 0.04 C vs. D). The MTT assay showed that dexamethasone had no direct effect on K12/TRb growth or on tumor FUdR sensitivity. Dexamethasone inhibited K12/TRb-induced angiogenesis in vivo.

CONCLUSIONS

Hepatic arterial dexamethasone is effective in treating colorectal hepatic metastases and is more effective when combined with hepatic arterial FUdR. The antiangiogenic activity of dexamethasone may partially contribute to its efficacy.

摘要

背景

一项治疗结直肠癌肝转移的随机试验表明，肝动脉注射氟尿苷（FUdR）联合地塞米松相比单纯肝动脉注射FUdR可提高肿瘤反应率（《癌症》，1992年；69：327 - 34）。这种改善的机制尚不清楚。

方法

我们在动物模型中研究了肝动脉注射地塞米松（无论是否联合FUdR）对结直肠癌肝转移生长的影响。在第0天，将10(7)个K12/TRb结肠癌细胞经脾内接种到BD - IX大鼠体内。在第14天，对肝转移灶进行计数，并放置肝动脉导管用于化疗。48只动物被随机分为4组，分别接受14天的单独肝素化盐水输注（A组）、含0.03 mg/kg/d地塞米松的肝素化盐水输注（B组）、含2 mg/kg/d FUdR的肝素化盐水输注（C组）或含0.03 mg/kg/d地塞米松加2 mg/kg/d FUdR的肝素化盐水输注（D组）。在第28天通过剖腹术再次对肝转移灶进行计数。每只大鼠的反应以第14天和第28天观察到的肝结节数量之间的肝结节数量变化百分比表示。使用MTT（3 - (4,5 - 二甲基噻唑 - 2 - 基)-2,5 - 二苯基四氮唑溴盐；美国密苏里州圣路易斯市西格玛公司）试验检测K12/TRb对含或不含地塞米松的FUdR的体外化学敏感性。使用体内试验检测地塞米松对肿瘤诱导的血管生成的影响。

结果

A组肿瘤结节的平均变化百分比为 +129%，B组为 +17%，C组为 -4%，D组为 -29%（A组与B组比较，p = 0.002；C组与D组比较，p = 0.04）。MTT试验表明，地塞米松对K12/TRb的生长或肿瘤对FUdR的敏感性没有直接影响。地塞米松在体内抑制K12/TRb诱导的血管生成。