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The tyrosine kinase inhibitor ZD6474 inhibits tumour growth in an intracerebral rat glioma model.

Sandström M, Johansson M, Andersson U, Bergh A, Bergenheim AT, Henriksson R - Br. J. Cancer (2004)

Bottom Line: ZD6474 significantly decreased tumour volume compared to controls.In vitro, the growth of both cell lines was significantly reduced.The results reported justify further experimental investigations concerning the effects of ZD6474 in malignant glioma alone or in combination with other modalities.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Sciences, Oncology, Umeå University, S-901 85 Umeå, Sweden. maria.sandstrom@onkologi.umu.se

ABSTRACT
Malignant glioma is characterised by extensive neovascularisation, principally influenced by vascular endothelial growth factor (VEGF). ZD6474 is a potent inhibitor of VEGF-R2 tyrosine kinase activity, but with additional inhibitory effects on other growth factors. In this study, we have investigated the effects of ZD6474 with regard to tumour growth, neovascularisation, proliferation and apoptosis in the intracerebral rat glioma model, BT4C. ZD6474 (50 and 100 mg kg(-1)) was given as a daily oral gavage. Animals were killed on day 19 and tumour volume was measured. Sections were stained for factor VIII, Ki-67 and for apoptosis. The ability of ZD6474 to inhibit cell growth directly was examined in vitro, using the glioma cell line BT4C and the transformed rat brain endothelial cell line RBE4. Cell growth was analysed with fluorometric microculture cytotoxicity assay to quantify the cytotoxic effects. ZD6474 significantly decreased tumour volume compared to controls. Microvascular density increased after treatment with ZD6474, and tumour cell proliferation index was reduced. There was also an increase in tumour cell apoptosis. In vitro, the growth of both cell lines was significantly reduced. The results reported justify further experimental investigations concerning the effects of ZD6474 in malignant glioma alone or in combination with other modalities.

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Assessment of mean vessel count was performed after immunohistochemical staining for factor VIII. Treatment with ZD6474 50 mg kg−1 resulted in increased mean vessel count from 94 (range 79–117) to 111 (range 104–126) vessels per high-power field (P=0.032). The higher dose ZD6474 100 mg kg−1 resulted in a mean vessel count of 112 (range 80–122) vessels per high-power field (P=0.36 compared to controls).
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fig5: Assessment of mean vessel count was performed after immunohistochemical staining for factor VIII. Treatment with ZD6474 50 mg kg−1 resulted in increased mean vessel count from 94 (range 79–117) to 111 (range 104–126) vessels per high-power field (P=0.032). The higher dose ZD6474 100 mg kg−1 resulted in a mean vessel count of 112 (range 80–122) vessels per high-power field (P=0.36 compared to controls).

Mentions: Apoptosis index increased in treated groups. In the control group, apoptosis index was 0.01 (range 0.01–0.02). The group treated with ZD6474 50 mg kg−1 had an apoptosis index at 0.03 (range 0.01–0.05) (P=0.022), and in the group treated with 100 mg kg−1, the apoptosis index was 0.02 (range 0.01–0.03) (P=0.022 compared to controls).


The tyrosine kinase inhibitor ZD6474 inhibits tumour growth in an intracerebral rat glioma model.

Sandström M, Johansson M, Andersson U, Bergh A, Bergenheim AT, Henriksson R - Br. J. Cancer (2004)

Assessment of mean vessel count was performed after immunohistochemical staining for factor VIII. Treatment with ZD6474 50 mg kg−1 resulted in increased mean vessel count from 94 (range 79–117) to 111 (range 104–126) vessels per high-power field (P=0.032). The higher dose ZD6474 100 mg kg−1 resulted in a mean vessel count of 112 (range 80–122) vessels per high-power field (P=0.36 compared to controls).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2747688&req=5

fig5: Assessment of mean vessel count was performed after immunohistochemical staining for factor VIII. Treatment with ZD6474 50 mg kg−1 resulted in increased mean vessel count from 94 (range 79–117) to 111 (range 104–126) vessels per high-power field (P=0.032). The higher dose ZD6474 100 mg kg−1 resulted in a mean vessel count of 112 (range 80–122) vessels per high-power field (P=0.36 compared to controls).
Mentions: Apoptosis index increased in treated groups. In the control group, apoptosis index was 0.01 (range 0.01–0.02). The group treated with ZD6474 50 mg kg−1 had an apoptosis index at 0.03 (range 0.01–0.05) (P=0.022), and in the group treated with 100 mg kg−1, the apoptosis index was 0.02 (range 0.01–0.03) (P=0.022 compared to controls).

Bottom Line: ZD6474 significantly decreased tumour volume compared to controls.In vitro, the growth of both cell lines was significantly reduced.The results reported justify further experimental investigations concerning the effects of ZD6474 in malignant glioma alone or in combination with other modalities.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Sciences, Oncology, Umeå University, S-901 85 Umeå, Sweden. maria.sandstrom@onkologi.umu.se

ABSTRACT
Malignant glioma is characterised by extensive neovascularisation, principally influenced by vascular endothelial growth factor (VEGF). ZD6474 is a potent inhibitor of VEGF-R2 tyrosine kinase activity, but with additional inhibitory effects on other growth factors. In this study, we have investigated the effects of ZD6474 with regard to tumour growth, neovascularisation, proliferation and apoptosis in the intracerebral rat glioma model, BT4C. ZD6474 (50 and 100 mg kg(-1)) was given as a daily oral gavage. Animals were killed on day 19 and tumour volume was measured. Sections were stained for factor VIII, Ki-67 and for apoptosis. The ability of ZD6474 to inhibit cell growth directly was examined in vitro, using the glioma cell line BT4C and the transformed rat brain endothelial cell line RBE4. Cell growth was analysed with fluorometric microculture cytotoxicity assay to quantify the cytotoxic effects. ZD6474 significantly decreased tumour volume compared to controls. Microvascular density increased after treatment with ZD6474, and tumour cell proliferation index was reduced. There was also an increase in tumour cell apoptosis. In vitro, the growth of both cell lines was significantly reduced. The results reported justify further experimental investigations concerning the effects of ZD6474 in malignant glioma alone or in combination with other modalities.

Show MeSH
Related in: MedlinePlus