Triple combination of irradiation, chemotherapy (pemetrexed), and VEGFR inhibition (SU5416) in human endothelial and tumor cells
| Autor: | Amir Abdollahi, Marc Bischof, Klaus J. Weber, Ping Gong, J.ürgen Debus, Peter E. Huber, Kenneth E. Lipson, Clemens Stoffregen |
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| Rok vydání: | 2004 |
| Předmět: |
Antimetabolites
Antineoplastic Cancer Research Pathology medicine.medical_specialty Guanine Indoles medicine.drug_class Angiogenesis Inhibitors Apoptosis Pemetrexed Antimetabolite Glutamates Cell Movement Cell Line Tumor Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Humans Pyrroles Radiology Nuclear Medicine and imaging Clonogenic assay Protein kinase B Tumor Stem Cell Assay Cell Proliferation Tube formation Matrigel Radiation Neovascularization Pathologic Cell growth business.industry Endothelial Cells Protein-Tyrosine Kinases Combined Modality Therapy Oncology Cancer research business medicine.drug |
| Zdroj: | International Journal of Radiation Oncology*Biology*Physics. 60:1220-1232 |
| ISSN: | 0360-3016 |
| DOI: | 10.1016/j.ijrobp.2004.07.689 |
| Popis: | Purpose: This is the first preclinical report evaluating a trimodal therapy consisting of irradiation, chemotherapy, and antiangiogenesis in the context of a multimodal anticancer strategy. The combination of the folate antimetabolite pemetrexed, SU5416, a receptor tyrosine kinase inhibitor of VEGFR2, and irradiation was investigated in human endothelial cells and tumor cell lines. Methods and materials: Primary isolated human umbilical vein endothelial cells (HUVEC), human dermal microvascular endothelial cells (HDMEC), and human glioblastoma (U87) and prostate cancer cells (PC3) were exposed to pemetrexed (2 h) alone and in combination with SU5416 (2 h). When combined with irradiation up to 8 Gy, fixed concentrations of pemetrexed (1.06 {mu}M) and SU5416 (1.0 {mu}M) were used. Proliferation and clonogenic assays were conducted with endothelial and tumor cells. The migration/invasion ability of endothelial cells and the ability to produce tubular structures were tested in Matrigel and tube formation assays. Apoptosis was measured by sub-G1 DNA and caspase-3 flow cytometry. To investigate underlying cell signaling, immunocytochemistry was used to detect Akt survival signaling involvement. Results: Triple combination using only a low-toxicity drug exposure of pemetrexed and SU5416 results in greater response than each treatment alone or than each combination of two modalities in all tested endothelialmore » and tumor cell models. Triple combination substantially inhibits proliferation, migration/invasion, tube formation, and clonogenic survival. Triple combination also induced the highest rate of apoptosis in HDMEC and HUVEC as indicated by sub-1 G1 and caspase-3 assessment. Interestingly, triple combination therapy also reduces proliferation and clonogenic survival significantly in U87 and PC3 tumor cell lines. SU5416 potently inhibited Akt phosphorylation which could be induced by radiation and radiochemotherapy in human endothelial cells. Conclusions: Our findings demonstrate the high antiendothelial/antitumoral efficacy of the concurrent administration of irradiation, chemotherapy, and angiogenesis inhibition in vitro. A potential explanation for the favorable combination would be that VEGF signaling inhibition downregulates Akt survival signaling upon activation by radiation and/or chemotherapy. The data also suggest that endothelial cell apoptosis may have an important role in the benefits of the presented therapy.« less |
| Databáze: | OpenAIRE |
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