Optimization of 5-FU metronomic chemotherapy strategy and regulation of the immune microenvironment in gastric cancer: an <italic style="font-style: italic">in vivo</italic> study

Jinling JIANG; Chenfei ZHOU; Wenqi XI; Min SHI; Mei GEN; Liqin ZHAO; Qu CAI; Jinsong JIANG; Jun ZHANG

doi:10.19401/j.cnki.1007-3639.2022.07.003

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Optimization of 5-FU metronomic chemotherapy strategy and regulation of the immune microenvironment in gastric cancer: an in vivo study

Article | 更新时间：2025-12-31

- Optimization of 5-FU metronomic chemotherapy strategy and regulation of the immune microenvironment in gastric cancer: an in vivo study
- China Oncology Vol. 32, Issue 7, Pages: 596-605(2022)
- 作者机构：
  
  1. 上海交通大学医学院附属瑞金医院肿瘤科,上海 200025
  2. 上海交通大学医学院附属瑞金医院无锡分院肿瘤科,江苏无锡 214021
- 作者简介：
  
  JIANG Jinsong, E-mail: jjs11039@rjh.com.cn.
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2022.07.003
  CLC： R735.2
- Received：10 June 2022，
  
  Published：30 July 2022
- 稿件说明：
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Jinling JIANG, Chenfei ZHOU, Wenqi XI, et al. Optimization of 5-FU metronomic chemotherapy strategy and regulation of the immune microenvironment in gastric cancer: an in vivo study[J]. China Oncology, 2022, 32(7): 596-605.
DOI：

Jinling JIANG, Chenfei ZHOU, Wenqi XI, et al. Optimization of 5-FU metronomic chemotherapy strategy and regulation of the immune microenvironment in gastric cancer: an in vivo study[J]. China Oncology, 2022, 32(7): 596-605. DOI： 10.19401/j.cnki.1007-3639.2022.07.003.

摘要

背景与目的：

5-氟尿嘧啶（5-fluorouracil

5-FU）是胃癌化疗的骨架药物

传统大剂量5-FU常导致严重不良反应及耐药。低剂量5-FU节拍化疗在不影响疗效的前提下可明显降低药物毒性

但何种给药节拍可达到最佳抗肿瘤作用尚不清楚。本研究旨在探索5-FU的最佳节拍化疗模式

并研究其对胃癌免疫微环境的影响。

方法：

建立SGC-7901胃癌细胞系的BALB/c裸小鼠皮下移植瘤模型

成瘤后随机分成4组：最大耐受剂量（maximum tolerated dose

MTD）组、每日节拍化疗（daily metronomic chemotherapy

MET-qd）组、隔日节拍化疗（every other day metronomic chemotherapy

MET-qod）组和每周2次节拍化疗（twice-weekly metronomic chemotherapy

MET-biw）组。21 d为1个疗程

共2个疗程。治疗期间观测裸小鼠的一般状况

每周称重并测量瘤体

绘制肿瘤生长曲线。采用流式细胞术检测裸小鼠外周血内皮祖细胞（circulating endothelial progenitors

CEP）

瘤体及脾脏内浸润的B细胞、自然杀伤（natural killer

NK）细胞、肿瘤相关巨噬细胞（tumor-associated macrophage

TAM）、髓源性抑制细胞（myeloid-derived suppressor cell

MDSC）。采

用免疫组织化学染色法检测瘤体内CD11c和CD163蛋白的表达。采用酶联免疫吸附法（enzyme-linked immunosorbent assay

ELISA）检测裸小鼠外周血中血管内皮生长因子（vascular endothelial growth factor

VEGF）、血小板源性生长因子（platelet derived growth factor

PDGF）、白细胞介素（interleukin

IL）-10和IL-12的表达。采用白细胞计数及H-E染色等评价肝、肺、肾和心脏毒性。

结果：

5-FU的3种节拍化疗模式均显示出与MTD组类似的抑制裸小鼠移植瘤生长效应

其中MET-qod组的抗肿瘤效应最明显（

0.05）。与MTD组（45.3%

#x000b1;4.3%）相比

5-FU的3种节拍化疗模式均可明显降低裸小鼠外周血的CEP数量

其中MET-qd组降低最明显（14.8%

#x000b1;3.8%）。外周血中VEGF在MET-qod组中下降最明显（

0.001）

而在MET-biw组中则明显升高（

0.001）。PDGF的表达与VEGF趋势基本一致。5-FU的3种节拍化疗模式与MTD组相比均可导致裸小鼠脾脏和瘤体内浸润的M1与M2型TAM比值增加

MET-qod组中该比值增加最显著（脾脏1.78

#x000b1;0.21

1.19

#x000b1;0.07;瘤体0.57

#x000b1;0.11

0.14

#x000b1;0.09;

0.001）。外周血中代表M2型TAM的IL-10在MET-qod中的表达量最少（

0.001）

代表M1型TAM的IL-12则相对高表达（

0.001）。与节拍化疗组相比

MTD组裸小鼠体重减轻、外周血白细胞及血小板绝对值明显减少（

0.001）

而3个节拍治疗组之间差异无统计学意义。MTD组裸小鼠的肺间质明显增厚和慢性炎症改变

类似表现在节拍化疗组中未见。

结论：

在不同的5-FU给药模式中

MET-qod节拍给药方式显示出最佳的抗肿瘤效应

且不增加不良反应。除抗血管生成外

还可通过调节TAM极化发挥抑瘤作用。

Abstract

Background and purpose:

5-fluorouracil (5-FU) is the backbone of drug for gastric cancer. Traditional high-dose 5-FU often leads to serious adverse reactions and drug resistance. The low-dose 5-FU metronomic chemotherapy can significantly reduce the toxicity of the drug without affecting the efficacy

but it is not clear which dose can achieve the best anti-tumor effect. The purpose of this study was to explore the optimal metronomic chemotherapy strategy for 5-FU and to explore the related molecular mechanisms.

Methods:

A nude mouse subcutaneous tumor model of SGC-7901 gastric cancer cell line was established. After tumor formation

mice were randomly divided into 4 groups: maximum tolerated dose (MTD) group

daily metronomic chemotherapy (MET-qd) group

every other day metronomic chemot

herapy (MET-qod) group and twice-weekly metronomic chemotherapy (MET-biw) group. Duration of single course of treatment was 21 d

and mice received a total of 2 courses of treatment. During the treatment period

the general condition of nude mice was observed

the tumor mass was weighed and measured every week

and the tumor growth curve was drawn. Flow cytometry was used to detect circulating endothelial progenitors (CEP) in peripheral blood of nude mice; B cells

natural killer (NK) cells

tumor-associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) infiltrated in the tumor and spleen. Immunohistochemical staining was used to detect the expressions of CD11c and CD163 in the tumor. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expressions of vascular endothelial growth factor (VEGF)

platelet derived growth factor (PDGF)

interleukin (IL)-10 and IL-12 in peripheral blood of nude mice. In addition

white blood cell counts and H-E stained sections of liver

lung

kidney

and heart were performed in order to monitor toxicity assessments.

Results:

The three metronomic chemotherapy strategies of 5-FU could inhibit the growth of xenograft tumor in nude mice similar to the MTD group

and the MET-qod group has the most obvious anti-tumor effect (

0.05). Compared with the MTD group (45.3%

#x000b1;4.3%)

the three metronomic chemotherapy strategies of 5-FU could significantly reduce the number of CEP in the peripheral blood of nude mice

among which the MET-qd group had the most significant decrease (14.8%

#x000b1;3.8%). VEGF in peripheral blood decreased most significantly in MET-qod group (

0.001)

but significantly increased in MET-biw group (

0.001). The expression of PDGF was consistent with the trend of VEGF. Compared with the MTD group

all three 5-FU metronomic chemotherapy strategies resulted in an increase in the ratio of M1 to M2 TAM infiltrated in the spleen and xenograft tumor of nude mice

and the ratio increased most significantly in the MET-qod group (spleen: 1.78

#x000b1;0.21

1.19

#x000b1;0.07; tumor: 0.57

#x000b1;0.11

0.14

#x000b1;0.09;

0.001). The expression of IL-10

which represented M2 TAM in peripheral blood

was the lowest in MET-qod group (

0.001)

while the expression of IL-12

which represented M1 TAM

was relatively high (

0.001). Compared with the metronomic chemotherapy group

the body weight of nude mice in MTD group decreased slightly

and the absolute values of peripheral blood leukocytes and platelets decreased significantly (

0.001)

however there was no statistically significant difference between the three metronomic treatment groups. The MTD group showed obvious thickening and chronic inflammatory changes in the pulmonary interstitium of nude mice

which were not found in the metronomic chemotherapy groups.

Conclusion:

The metronomic administration of 5-FU MET-qod can achieve the best antitumor effect without increasing toxicity. In addition to anti-angiogenesis

it also exerts its anti-tumor effect by regulating the polarization of TAM.

关键词

Keywords

references

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Optimization of 5-FU metronomic chemotherapy strategy and regulation of the immune microenvironment in gastric cancer: an in vivo study

DOI：10.19401/j.cnki.1007-3639.2022.07.003

摘要

Abstract

关键词

Keywords

references