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Modeling Brain Metastasis by Internal Carotid Artery Injection of Cancer Cells
Published on: August 2, 2022
Antitumor activity of ZD6474 in a metastatic orthotopic brain tumor model
Doo-Sik Kong1, Mi-Hyun Kim, Ji-Won Jeon
1Department of Neurosurgery, Samsung Medical Center and Samsung Biochemical Research Institute, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
Abstract:
The objective of this study was to examine the antitumor effect of ZD6474, an orally available inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR-2) and the epidermal growth factor receptor (EGFR), on tumor growth in an orthotopic metastatic brain tumor model. In order to determine the antitumor mechanism of ZD6474 treatment, in vitro and in vivo studies were performed. Human breast carcinoma cells (MDA-MB-435) were injected using direct intracranial (IC) inoculation (5x105 cells/100 µl) and internal carotid artery (ICA) injection (5x104 cells/100 µl) in Balb/c-nu female mice. Daily oral treatment with ZD6474 (50 mg/kg) was initiated on day 14 after the establishment of micrometastasis. Mice (n=12 per group) were sacrificed on day 28. Western blot analysis revealed that the autophosphorylation of EGFR and Akt was increasingly decreased with ZD6474 treatment in lung and brain endothelial cells and the MDA-MB-435 cell line. MTT assay also showed that the in vitro antitumor activity of ZD6474 was dependent on EGFR tyrosine kinase inhibition at a higher dose. Daily oral treatment with ZD6474 led to marked inhibition of metastatic tumor growth in the ICA injection and the direct IC inoculation models (median size 3.5 mm3, range 1.6-13.9 mm3) as compared to the control group (median size 62.4 mm3, range 11.5-206.9 mm3). These results suggest that simultaneous inhibition of both the EGFR and VEGFR-2 signaling pathways has a valuable therapeutic effect through its inhibition of the growth of metastatic brain tumors.
Insights
ZD6474, a dual inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR), effectively reduced brain tumor growth in mice. This study highlights the therapeutic potential of targeting both EGFR and VEGFR-2 signaling pathways for metastatic brain tumors.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Metastatic brain tumors pose a significant therapeutic challenge.
- Targeting receptor tyrosine kinases like EGFR and VEGFR-2 is a promising strategy for cancer treatment.
Purpose of the Study:
- To evaluate the antitumor efficacy of ZD6474, an orally available inhibitor of VEGFR-2 and EGFR.
- To investigate the underlying antitumor mechanisms of ZD6474 in an orthotopic brain tumor model.
Main Methods:
- Orthotopic brain tumor models were established in mice using human breast carcinoma cells (MDA-MB-435) via intracranial and internal carotid artery injections.
- Mice received daily oral treatment with ZD6474 (50 mg/kg).
- Western blot and MTT assays were used to assess molecular changes and in vitro antitumor activity.
Main Results:
- ZD6474 treatment significantly decreased the autophosphorylation of EGFR and Akt in tumor cells and endothelial cells.
- In vitro studies indicated that ZD6474's antitumor activity was dependent on EGFR tyrosine kinase inhibition.
- ZD6474 markedly inhibited metastatic tumor growth in both intracranial and internal carotid artery injection models compared to controls.
Conclusions:
- Simultaneous inhibition of EGFR and VEGFR-2 signaling pathways by ZD6474 demonstrates significant therapeutic potential.
- ZD6474 effectively inhibits the growth of metastatic brain tumors.
- Targeting both EGFR and VEGFR-2 pathways offers a valuable therapeutic approach for brain metastases.
