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Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models.
- Source :
-
British Journal of Cancer . 8/22/2017, Vol. 117 Issue 5, p628-638. 11p. 1 Diagram, 1 Chart, 5 Graphs. - Publication Year :
- 2017
-
Abstract
- <bold>Background: </bold>Lurbinectedin is a novel anticancer agent currently undergoing late-stage (Phase II /III) clinical evaluation in platinum-resistant ovarian, BRCA1/2-mutated breast and small-cell lung cancer. Lurbinectedin is structurally related to trabectedin and it inhibits active transcription and the DNA repair machinery in tumour cells.<bold>Methods: </bold>In this study we investigated whether lurbinectedin has the ability to modulate the inflammatory microenvironment and the viability of myeloid cells in tumour-bearing mice.<bold>Results: </bold>Administration of lurbinectedin significantly and selectively decreased the number of circulating monocytes and, in tumour tissues, that of macrophages and vessels. Similar findings were observed when a lurbinectedin-resistant tumour variant was used, indicating a direct effect of lurbinectedin on the tumour microenviroment. In vitro, lurbinectedin induced caspase-8-dependent apoptosis of human purified monocytes, whereas at low doses it significantly inhibited the production of inflammatory/growth factors (CCL2, CXCL8 and VEGF) and dramatically impaired monocyte adhesion and migration ability. These findings were supported by the strong inhibition of genes of the Rho-GTPase family in lurbinectedin-treated monocytes.<bold>Conclusions: </bold>The results illustrate that lurbinectedin affects at multiple levels the inflammatory microenvironment by acting on the viability and functional activity of mononuclear phagocytes. These peculiar effects, combined with its intrinsic activity against cancer cells, make lurbinectedin a compound of particular interest in oncology. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PROTEIN metabolism
*ANIMALS
*ANTINEOPLASTIC agents
*APOPTOSIS
*BIOCHEMISTRY
*CARRIER proteins
*CELL physiology
*CELL motility
*GENE expression
*HETEROCYCLIC compounds
*INFLAMMATORY mediators
*INTERLEUKINS
*ISOQUINOLINE
*MACROPHAGES
*PHENOMENOLOGY
*MICE
*MONOCYTES
*OVARIAN tumors
*PYRIDINE
*RESEARCH funding
*VASCULAR endothelial growth factors
*GENE expression profiling
*LEUKOCYTE count
*PATHOLOGIC neovascularization
*PHARMACODYNAMICS
*PHYSIOLOGY
*THERAPEUTICS
CONNECTIVE tissue tumors
Subjects
Details
- Language :
- English
- ISSN :
- 00070920
- Volume :
- 117
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- British Journal of Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 124754046
- Full Text :
- https://doi.org/10.1038/bjc.2017.205