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低剂量抗肿瘤药物通过肿瘤组织中的骨髓来源细胞促进肿瘤血管生成和生长。

Promotion of tumor angiogenesis and growth induced by low-dose antineoplastic agents via bone-marrow-derived cells in tumor tissues.

作者信息

You Huining, Zhao Peipei, Zhao Xue, Zheng Qiaowei, Ma Wenbing, Cheng Kai, Li Min, Kou Jianrong, Feng Weiyi

机构信息

Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

出版信息

Front Pharmacol. 2024 Jul 25;15:1414832. doi: 10.3389/fphar.2024.1414832. eCollection 2024.

DOI:10.3389/fphar.2024.1414832
PMID:39119610
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11306047/
Abstract

BACKGROUND

More research is needed to solidify the basis for reasonable metronomic chemotherapy regimens due to the inconsistent clinical outcomes from studies on metronomic chemotherapy with antineoplastic agents, along with signs of a nonlinear dose-response relationship at low doses. The present study therefore explored the dose-response relationships of representative antineoplastic agents in low dose ranges and their underlying mechanisms.

METHODS

Cyclophosphamide (CPA) and 5-fluorouracil (5-Fu) were employed to observe the effects of the frequent administration of low-dose antineoplastic agents on tumor growth, tumor angiogenesis, and bone-marrow-derived cell (BMDC) mobilization in mouse models. The effects of antineoplastic agents on tumor and endothelial cell functions with or without BMDCs were analyzed .

RESULTS

Tumor growth and metastasis were significantly promoted after the administration of CPA or 5-Fu at certain low dose ranges, and were accompanied by enhanced tumor angiogenesis and proangiogenic factor expression in tumor tissues, increased proangiogenic BMDC release in the circulating blood, and augmented proangiogenic BMDC retention in tumor tissues. Low concentrations of CPA or 5-Fu were found to significantly promote tumor cell migration and invasion, and enhance BMDC adhesion to endothelial cells .

CONCLUSION

These results suggest that there are risks in empirical metronomic chemotherapy using low-dose antineoplastic agents and the optimal dosage and administration schedule of antineoplastic agents need to be determined through further research.

摘要

背景

由于使用抗肿瘤药物进行节拍化疗的研究临床结果不一致，且在低剂量时存在非线性剂量反应关系的迹象，因此需要更多研究来巩固合理节拍化疗方案的基础。因此，本研究探讨了代表性抗肿瘤药物在低剂量范围内的剂量反应关系及其潜在机制。

方法

使用环磷酰胺（CPA）和5-氟尿嘧啶（5-Fu）观察低剂量抗肿瘤药物频繁给药对小鼠模型中肿瘤生长、肿瘤血管生成和骨髓来源细胞（BMDC）动员的影响。分析了抗肿瘤药物在有无BMDC情况下对肿瘤和内皮细胞功能的影响。

结果

在一定低剂量范围内给予CPA或5-Fu后，肿瘤生长和转移显著促进，同时肿瘤组织中的肿瘤血管生成和促血管生成因子表达增强，循环血液中促血管生成BMDC释放增加，肿瘤组织中促血管生成BMDC滞留增加。发现低浓度的CPA或5-Fu可显著促进肿瘤细胞迁移和侵袭，并增强BMDC与内皮细胞的粘附。

结论

这些结果表明，使用低剂量抗肿瘤药物进行经验性节拍化疗存在风险，需要通过进一步研究确定抗肿瘤药物的最佳剂量和给药方案。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/bda9ff6bc6b3/fphar-15-1414832-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/fabdf5413355/fphar-15-1414832-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/11dc795134d7/fphar-15-1414832-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/44e4dadc46f2/fphar-15-1414832-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/99b5886e8cd6/fphar-15-1414832-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/f3d2c8b2c75d/fphar-15-1414832-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/9aa1d00f8f3f/fphar-15-1414832-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/b087223b9313/fphar-15-1414832-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/bda9ff6bc6b3/fphar-15-1414832-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/fabdf5413355/fphar-15-1414832-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/11dc795134d7/fphar-15-1414832-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/44e4dadc46f2/fphar-15-1414832-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/99b5886e8cd6/fphar-15-1414832-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/f3d2c8b2c75d/fphar-15-1414832-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/9aa1d00f8f3f/fphar-15-1414832-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/b087223b9313/fphar-15-1414832-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/11306047/bda9ff6bc6b3/fphar-15-1414832-g008.jpg

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