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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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In vitro effect of vinorelbine on A498 and 786-O cell cycle regulation and cell cycle protein expression. (A) Three different doses of vinorelbine were used to assess the effect of vinorelbine on cell cycle regulation in A498 and 786-O cells. At a 100 nM dose, a significant G2/M phase arrest (P < 0.01 compared to untreated cells) was observed in A498, whereas 786-O cells arrested at the G2/M phase with a 10 nM dose of vinorelbine. **, P < 0.01(treated group versus control group). (B) When A498 and 786-O cells were treated with vinorelbine for 72 hrs and 48 hrs, respectively, increased Cyclin B1, phospho-histone H3, and Cdk1 were detected with doses of 100 nM and 10 nM of vinorelbine in A498 and 786-O tumours cells, respectively. In both cell lines, Cyclin A was decreased with a 1 μM dose. PCNA expression did not change with any treatments. In each case, β-Actin was used as a loading control.
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fig02: In vitro effect of vinorelbine on A498 and 786-O cell cycle regulation and cell cycle protein expression. (A) Three different doses of vinorelbine were used to assess the effect of vinorelbine on cell cycle regulation in A498 and 786-O cells. At a 100 nM dose, a significant G2/M phase arrest (P < 0.01 compared to untreated cells) was observed in A498, whereas 786-O cells arrested at the G2/M phase with a 10 nM dose of vinorelbine. **, P < 0.01(treated group versus control group). (B) When A498 and 786-O cells were treated with vinorelbine for 72 hrs and 48 hrs, respectively, increased Cyclin B1, phospho-histone H3, and Cdk1 were detected with doses of 100 nM and 10 nM of vinorelbine in A498 and 786-O tumours cells, respectively. In both cell lines, Cyclin A was decreased with a 1 μM dose. PCNA expression did not change with any treatments. In each case, β-Actin was used as a loading control.

Mentions: Regulators of cell cycle phase transitions could be important targets for cancer treatment using cytostatic chemotherapy. There are several reports describing the effect of vinca alkaloids on cell cycle phase perturbations and on vinorelbine treatment causing general G2/M phase arrest [24, 26]. Cell cycle analysis with different concentrations of vinorelbine treatments in A498 cells is shown in Fig. 2A. A 100 nM concentration of vinorelbine led to increases in both the G2/M (P < 0.01) as well as S-phase (P < 0.01) fractions, whereas only a 10 nM dose caused significant G2/M arrest in 786-O cells (P < 0.01). There was also a moderate increase in the S-phase fraction of 786-O cells after a 10 nM vinorelbine treatment (Fig. 2A).


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)

In vitro effect of vinorelbine on A498 and 786-O cell cycle regulation and cell cycle protein expression. (A) Three different doses of vinorelbine were used to assess the effect of vinorelbine on cell cycle regulation in A498 and 786-O cells. At a 100 nM dose, a significant G2/M phase arrest (P < 0.01 compared to untreated cells) was observed in A498, whereas 786-O cells arrested at the G2/M phase with a 10 nM dose of vinorelbine. **, P < 0.01(treated group versus control group). (B) When A498 and 786-O cells were treated with vinorelbine for 72 hrs and 48 hrs, respectively, increased Cyclin B1, phospho-histone H3, and Cdk1 were detected with doses of 100 nM and 10 nM of vinorelbine in A498 and 786-O tumours cells, respectively. In both cell lines, Cyclin A was decreased with a 1 μM dose. PCNA expression did not change with any treatments. In each case, β-Actin was used as a loading control.
© Copyright Policy
Related In: Results  -  Collection

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

fig02: In vitro effect of vinorelbine on A498 and 786-O cell cycle regulation and cell cycle protein expression. (A) Three different doses of vinorelbine were used to assess the effect of vinorelbine on cell cycle regulation in A498 and 786-O cells. At a 100 nM dose, a significant G2/M phase arrest (P < 0.01 compared to untreated cells) was observed in A498, whereas 786-O cells arrested at the G2/M phase with a 10 nM dose of vinorelbine. **, P < 0.01(treated group versus control group). (B) When A498 and 786-O cells were treated with vinorelbine for 72 hrs and 48 hrs, respectively, increased Cyclin B1, phospho-histone H3, and Cdk1 were detected with doses of 100 nM and 10 nM of vinorelbine in A498 and 786-O tumours cells, respectively. In both cell lines, Cyclin A was decreased with a 1 μM dose. PCNA expression did not change with any treatments. In each case, β-Actin was used as a loading control.
Mentions: Regulators of cell cycle phase transitions could be important targets for cancer treatment using cytostatic chemotherapy. There are several reports describing the effect of vinca alkaloids on cell cycle phase perturbations and on vinorelbine treatment causing general G2/M phase arrest [24, 26]. Cell cycle analysis with different concentrations of vinorelbine treatments in A498 cells is shown in Fig. 2A. A 100 nM concentration of vinorelbine led to increases in both the G2/M (P < 0.01) as well as S-phase (P < 0.01) fractions, whereas only a 10 nM dose caused significant G2/M arrest in 786-O cells (P < 0.01). There was also a moderate increase in the S-phase fraction of 786-O cells after a 10 nM vinorelbine treatment (Fig. 2A).

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