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Linomide blocks angiogenesis by breast carcinoma vascular endothelial growth factor transfectants
M Ziche1, S Donnini, L Morbidelli
1Department of Pharmacology, University of Florence, Italy.
Abstract:
The blocking of angiogenesis provides a novel therapeutic target to inhibit tumour spreading. In this study, we investigated the effect of linomide on angiogenesis induced in vivo by highly angiogenic breast carcinoma cells. The rabbit cornea was used to assess neovascular growth in the absence of a tumour mass. MCF-7 cells stably transfected with the cDNA encoding for vascular endothelial growth factor 121 (VEGF121) (V12 clone) were used to elicit a potent VEGF-dependent corneal angiogenesis. After tumour cell implant, albino rabbits received 100 mg kg(-1) day(-1) linomide for 5 consecutive days. Daily observation of neovascular progression indicated that linomide blocked angiogenesis. The antiangiogenic effect of linomide was apparent within 48 h from the beginning of the treatment and was both angiosuppressive and angiostatic. The block of neovascular growth lasted over 10 days from treatment suspension, and preformed vessels, which had regressed, remained dormant, suggesting the persistence of unfavourable conditions for capillary progression. Linomide (50-200 microg ml[-1]) was not cytotoxic in vitro on resting capillary endothelial cells but blocked endothelial cell replication induced by VEGF. Our data indicate that linomide can efficiently and persistently block VEGF-dependent angiogenesis in vivo in the absence of a growing tumour mass. These data suggest that linomide could be a chemopreventive drug in breast cancer patients and a valuable tool in clinical settings in which metastatic spreading occurs in the absence of a detectable tumour mass.
Insights
Linomide effectively blocks tumor-induced angiogenesis, preventing blood vessel growth without harming healthy cells. This suggests its potential as a chemopreventive drug for breast cancer and managing metastasis.
Area of Science:
- Oncology
- Vascular Biology
- Pharmacology
Background:
- Angiogenesis, the formation of new blood vessels, is crucial for tumor growth and metastasis.
- Blocking angiogenesis presents a therapeutic strategy to inhibit tumor spread.
- Vascular Endothelial Growth Factor (VEGF) is a key driver of tumor angiogenesis.
Purpose of the Study:
- To investigate the anti-angiogenic effects of linomide.
- To assess linomide's impact on VEGF-driven angiogenesis in vivo.
- To evaluate linomide's potential as a chemopreventive agent for breast cancer.
Main Methods:
- Utilized the rabbit cornea model to study in vivo angiogenesis.
- Induced angiogenesis using MCF-7 breast carcinoma cells engineered to overexpress VEGF121.
- Administered linomide to rabbits and observed neovascularization progression.
- Assessed linomide's cytotoxicity and effect on endothelial cell replication in vitro.
Main Results:
- Linomide significantly blocked VEGF-dependent corneal angiogenesis.
- The anti-angiogenic effect was observed within 48 hours and persisted after treatment cessation.
- Linomide demonstrated angiosuppressive and angiostatic properties.
- In vitro studies showed linomide inhibited VEGF-induced endothelial cell replication without cytotoxicity.
Conclusions:
- Linomide effectively and persistently blocks VEGF-dependent angiogenesis in vivo.
- Linomide shows promise as a chemopreventive drug for breast cancer.
- Linomide may be a valuable therapeutic tool for managing metastatic spread, even without a detectable tumor mass.