| HUI CAO,Shili Wang,Yaohui Liu. Antitumor and vascular effects of apatinib combined with chemotherapy in mice with non-small-cell lung cancer. Oncol Transl Med, 2021, 7: 141-147. |
| 阿帕替尼联合化疗对非小细胞肺癌小鼠的抗肿瘤作用及血管效应的实验研究 |
| Antitumor and vascular effects of apatinib combined with chemotherapy in mice with non-small-cell lung cancer |
| Received:November 03, 2020 Revised:June 22, 2021 |
| DOI：10.1007/s10330-020-0465-5 |
| 中文关键词: 非小细胞肺癌；阿帕替尼；培美曲塞 |
| 英文关键词: non-small-cell lung cancer (NSCLC); apatinib; pemetrexed |
| 基金项目: |
| Author Name | Affiliation | E-mail | | HUI CAO* | Department of Pharmacy, Zigong Fourth People''s Hospital, Zigong 643000, China | benbenda3321@163.com | | Shili Wang | Department of Pharmacy, Zigong Fourth People''s Hospital, Zigong 643000, China | | | Yaohui Liu | Department of Pharmacy, Zigong First People''s Hospital, Zigong 643000, China | |
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| 中文摘要: |
| 目的：探讨阿帕替尼联合化疗对非小细胞肺癌(NSCLC)小鼠的抗肿瘤作用及血管效应。方法：小鼠实验由两部分构成，第一部分，将60只BALB/c荷瘤裸鼠随机分为Control组、低剂量(60mg/Kg)阿帕替尼组和高剂量(120mg/Kg)阿帕替尼组，在给药前、给药后第1d、3d、7d、10d每组各处死4只小鼠。利用免疫组化检测肿瘤组织中的HIF-1α表达，电镜下观察肿瘤血管超微结构。第二部分，将32只BALB/c荷瘤裸鼠随机分为对照组、培美曲塞组、阿帕替尼与培美曲塞同步组、阿帕替尼序贯培美曲塞组。连续用药14d，记录小鼠体重和肿瘤体积。利用Western blot检测相关信号通路蛋白的表达。结果：（1）经小剂量阿帕替尼治疗后，HIF-1α在治疗第3d和第7d表达水平明显降低。高剂量阿帕替尼组各时间点HIF-1α的表达量无明显差异(P>0.05)。Western-blot检测显示，与其他组相比，小剂量阿帕替尼组移植瘤组织中MMP-2和MMP-9的表达水平在治疗第3-7d期间显著降低(P<0.05)。其他时间点或高剂量阿帕替尼组的MMP-2、MMP-9表达水平均无明显变化(P>0.05)。（2）小剂量阿帕替尼组治疗后第3~7天，微血管密度(MVD)水平逐渐升高，其他时间段差异无统计学意义（P＞0.05）。大剂量阿帕替尼组的MVD明显降低。（3）与对照组相比，其余三组移植瘤的生长均受到明显抑制。小剂量阿帕替尼联合培美曲塞序贯治疗的肿瘤抑制效果最好，而同步治疗的组抑瘤效果并不优于培美曲塞单一治疗。（4）序贯组移植瘤组织中p-AKT、p-mTOR、P-MEK和p-ERK的表达水平明显低于其他三组，差异具有统计学意义(P＜0.05)。结论：阿帕替尼治疗裸鼠NSCLC时有一定的血管正常化的剂量要求和时间窗，这提示临床可利用DCE-MRI等检查可以用来确定患者血管正常化的窗口，以达到最佳抗血管疗效。 |
| 英文摘要: |
| Objective The aim of this study was to investigate the antitumor and vascular effects of apatinib use
combined with chemotherapy on mice with non-small-cell lung cancer (NSCLC).
Methods First, 60 tumor-bearing nude mice were randomly divided into control, low-dose, and high-dose
groups. Four nude mice per group were sacrificed before administration and on days 1, 3, 7, and 10 after
administration. HIF-1α expression in tumor tissues was detected. Second, 32 nude mice were randomly
divided into control, premetrexed, synchronous, and sequential groups. The weights and tumor volumes of
mice were recorded.
Results (1) HIF-1α expression decreased significantly on days 3 and 7 after low-dose apatinib treatment.
There was no significant difference in HIF-1α expression in the high-dose apatinib group (P > 0.05). MMP-
2 and MMP-9 expression levels in the low-dose apatinib group were significantly lower than those in the
control group (P < 0.05). (2) In the low-dose apatinib group, the microvessel density increased gradually
from days 3 to 7 post-treatment, while that in the high-dose apatinib group decreased significantly. (3) The
inhibitory effect of sequential therapy using low-dose apatinib and pemetrexed was optimal, while that of
synchronous treatment was not better than that of pemetrexed usage alone. Sequential treatment using
low-dose apatinib and pemetrexed exerted the best antitumor effect. (4) The expression levels of p-AKT,
p-mTOR, p-MEK, and p-ERK in the sequential group were significantly lower than those in the other three
groups (P < 0.05).
Conclusion Apatinib usage involves certain considerations, such as dose requirements and time window
for vascular normalization during lung cancer treatment in nude mice, suggesting that dynamic contrastenhanced magnetic resonance imaging and other tests can be conducted to determine the vascular
normalization window in patients with lung cancer and to achieve the optimal anti-vascular effect. |
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