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VEGF neutralizing antibody increases the therapeutic efficacy of vinorelbine for renal cell carcinoma.

Sinha S, Cao Y, Dutta S, Wang E, Mukhopadhyay D - J. Cell. Mol. Med. (2008)

Bottom Line: For this reason, the aim of our study is to develop a more effective combinational therapy to treat advanced RCC.We examined the effect of vinorelbine on the signalling pathways of two human renal cancer cell lines (A498 and 786-O) and also examined the in vivo effect of vinorelbine treatment alone and vinorelbine in combination with the anti-VEGF antibody 2C3 on A498 and 786-O tumour growth in nude mice.The results suggest a breakthrough treatment for advanced RCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

ABSTRACT
Renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies and affects approximately three in 10,000 people. The impact of this disease produces about 31,000 new cases in the United States per year; and 12,000 people in the United States alone die from RCC annually. Although several treatment strategies have been investigated for RCC, this cancer continues to be a therapeutic challenge. For this reason, the aim of our study is to develop a more effective combinational therapy to treat advanced RCC. We examined the effect of vinorelbine on the signalling pathways of two human renal cancer cell lines (A498 and 786-O) and also examined the in vivo effect of vinorelbine treatment alone and vinorelbine in combination with the anti-VEGF antibody 2C3 on A498 and 786-O tumour growth in nude mice. Tumour angiogenesis was measured by vWF staining, and apoptosis was determined by the TUNEL assay. We observed a significant tumour growth inhibition when using a combinational therapy of anti-VEGF antibody 2C3 and vinorelbine in both A498 and 786-O tumour-bearing mice. The results suggest a breakthrough treatment for advanced RCC.

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Effect of vinorelbine on A498 and 786-O apoptosis, Akt phosphorylation and caspase activity in vitro. (A) A498 and 786-O apoptosis were measured following treatment with different doses of vinorelbine after 72 hrs and 48 hrs, respectively, by the Annexin/PI method. At a 100 nM concentration, significantly higher levels of Annexin/PI staining were recorded in vinorelbine-treated A498 cells (P < 0.01). In 786-O renal cancer cells, only 10 nM dose of vinorelbine induced significant apoptosis (P < 0.01). **, P < 0.01(treated group versus control group). (B) After A498 cells were treated with vinorelbine for 72 hrs, a down-regulation of Akt phosphorylation was observed in the 100 nM treatment group. In 786-O, a marked down-regulation in Akt phosphorylation was observed at a 1.0 μM dose after 48 hrs of treatment. Total Akt1 was used as a loading control. (C) A498 and 786-O cells were treated with vinorelbine for 72 hrs and 48 hrs, respectively, and increased caspase-3 and -9 activity was detected in the 100 nM and 1.0 μM dose treatment groups of A498 and 786-O, respectively. β-Actin was used as a loading control.
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fig04: Effect of vinorelbine on A498 and 786-O apoptosis, Akt phosphorylation and caspase activity in vitro. (A) A498 and 786-O apoptosis were measured following treatment with different doses of vinorelbine after 72 hrs and 48 hrs, respectively, by the Annexin/PI method. At a 100 nM concentration, significantly higher levels of Annexin/PI staining were recorded in vinorelbine-treated A498 cells (P < 0.01). In 786-O renal cancer cells, only 10 nM dose of vinorelbine induced significant apoptosis (P < 0.01). **, P < 0.01(treated group versus control group). (B) After A498 cells were treated with vinorelbine for 72 hrs, a down-regulation of Akt phosphorylation was observed in the 100 nM treatment group. In 786-O, a marked down-regulation in Akt phosphorylation was observed at a 1.0 μM dose after 48 hrs of treatment. Total Akt1 was used as a loading control. (C) A498 and 786-O cells were treated with vinorelbine for 72 hrs and 48 hrs, respectively, and increased caspase-3 and -9 activity was detected in the 100 nM and 1.0 μM dose treatment groups of A498 and 786-O, respectively. β-Actin was used as a loading control.

Mentions: A therapeutic approach will most likely require a drug-mediated induction of apoptotic activity on the cancer cell. Figure 4A describes apoptosis measurement using Annexin/PI. We observed a dose-dependent induction of apoptosis in A498 and 786-O cells after vinorelbine treatment. A 100 nM dose of the drug induced significant apoptosis in A498 cells, whereas in 786-O cells only a 10 nM dose of vinorelbine was sufficient to induce marked apoptosis. No induction in apoptosis was observed when treating with 2C3 (data not shown).


VEGF neutralizing antibody increases the therapeutic efficacy of vinorelbine for renal cell carcinoma.

Sinha S, Cao Y, Dutta S, Wang E, Mukhopadhyay D - J. Cell. Mol. Med. (2008)

Effect of vinorelbine on A498 and 786-O apoptosis, Akt phosphorylation and caspase activity in vitro. (A) A498 and 786-O apoptosis were measured following treatment with different doses of vinorelbine after 72 hrs and 48 hrs, respectively, by the Annexin/PI method. At a 100 nM concentration, significantly higher levels of Annexin/PI staining were recorded in vinorelbine-treated A498 cells (P < 0.01). In 786-O renal cancer cells, only 10 nM dose of vinorelbine induced significant apoptosis (P < 0.01). **, P < 0.01(treated group versus control group). (B) After A498 cells were treated with vinorelbine for 72 hrs, a down-regulation of Akt phosphorylation was observed in the 100 nM treatment group. In 786-O, a marked down-regulation in Akt phosphorylation was observed at a 1.0 μM dose after 48 hrs of treatment. Total Akt1 was used as a loading control. (C) A498 and 786-O cells were treated with vinorelbine for 72 hrs and 48 hrs, respectively, and increased caspase-3 and -9 activity was detected in the 100 nM and 1.0 μM dose treatment groups of A498 and 786-O, respectively. β-Actin was used as a loading control.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2992850&req=5

fig04: Effect of vinorelbine on A498 and 786-O apoptosis, Akt phosphorylation and caspase activity in vitro. (A) A498 and 786-O apoptosis were measured following treatment with different doses of vinorelbine after 72 hrs and 48 hrs, respectively, by the Annexin/PI method. At a 100 nM concentration, significantly higher levels of Annexin/PI staining were recorded in vinorelbine-treated A498 cells (P < 0.01). In 786-O renal cancer cells, only 10 nM dose of vinorelbine induced significant apoptosis (P < 0.01). **, P < 0.01(treated group versus control group). (B) After A498 cells were treated with vinorelbine for 72 hrs, a down-regulation of Akt phosphorylation was observed in the 100 nM treatment group. In 786-O, a marked down-regulation in Akt phosphorylation was observed at a 1.0 μM dose after 48 hrs of treatment. Total Akt1 was used as a loading control. (C) A498 and 786-O cells were treated with vinorelbine for 72 hrs and 48 hrs, respectively, and increased caspase-3 and -9 activity was detected in the 100 nM and 1.0 μM dose treatment groups of A498 and 786-O, respectively. β-Actin was used as a loading control.
Mentions: A therapeutic approach will most likely require a drug-mediated induction of apoptotic activity on the cancer cell. Figure 4A describes apoptosis measurement using Annexin/PI. We observed a dose-dependent induction of apoptosis in A498 and 786-O cells after vinorelbine treatment. A 100 nM dose of the drug induced significant apoptosis in A498 cells, whereas in 786-O cells only a 10 nM dose of vinorelbine was sufficient to induce marked apoptosis. No induction in apoptosis was observed when treating with 2C3 (data not shown).

Bottom Line: For this reason, the aim of our study is to develop a more effective combinational therapy to treat advanced RCC.We examined the effect of vinorelbine on the signalling pathways of two human renal cancer cell lines (A498 and 786-O) and also examined the in vivo effect of vinorelbine treatment alone and vinorelbine in combination with the anti-VEGF antibody 2C3 on A498 and 786-O tumour growth in nude mice.The results suggest a breakthrough treatment for advanced RCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

ABSTRACT
Renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies and affects approximately three in 10,000 people. The impact of this disease produces about 31,000 new cases in the United States per year; and 12,000 people in the United States alone die from RCC annually. Although several treatment strategies have been investigated for RCC, this cancer continues to be a therapeutic challenge. For this reason, the aim of our study is to develop a more effective combinational therapy to treat advanced RCC. We examined the effect of vinorelbine on the signalling pathways of two human renal cancer cell lines (A498 and 786-O) and also examined the in vivo effect of vinorelbine treatment alone and vinorelbine in combination with the anti-VEGF antibody 2C3 on A498 and 786-O tumour growth in nude mice. Tumour angiogenesis was measured by vWF staining, and apoptosis was determined by the TUNEL assay. We observed a significant tumour growth inhibition when using a combinational therapy of anti-VEGF antibody 2C3 and vinorelbine in both A498 and 786-O tumour-bearing mice. The results suggest a breakthrough treatment for advanced RCC.

Show MeSH
Related in: MedlinePlus