Wide Spectrum of Antitumor Activity of a Neutralizing Monoclonal Antibody to Human Vascular Endothelial Growth Factor

Asano, Makoto; Yukita, Ayako; Suzuki, Hideo

doi:10.1111/j.1349-7006.1999.tb00671.x

Cited by 52 publications

(29 citation statements)

References 30 publications

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“…[8][9][10][11][12][13][14][15][16][17] In animal models, VEGF suppression inhibited the tumor growth, whereas overexpression of VEGF enhanced tumor growth. [18][19][20][21][22][23][24][25][26][27]65 VEGF has also been shown to act as a survival factor for retinal and tumor vasculature and as a marker of tumor endothelium. 47,48 HCC is responsible for approximately 27,000 fatalities a year in Japan, and represents the third and fourth most frequent causes of malignant neoplasm-related deaths in males and females, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10][11][12][13][14][15][16][17] In animal models, overexpression of VEGF has been shown to enhance tumor growth, whereas suppression of VEGF inhibited tumor growth in several types of tumors. [18][19][20][21][22][23][24][25][26] The Tet system is a novel drug-regulated gene expression system by which the gene of interest can be changed in an ''on and off'' manner. 28 By delivering the VEGF gene by this modified system, VEGF gene expression of in vivo tumors can be controlled by administering tetracycline in the drinking water, which cannot be achieved by the conventional gene expression system.…”

mentioning

confidence: 99%

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KDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells

Yoshiji

Kuriyama

Hicklin³

et al. 1999

Hepatology

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

KDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells

Yoshiji

Kuriyama

Hicklin³

et al. 1999

Hepatology

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“…The degree of efficacy of VEGF suppression by an anti-VEGF antibody or a VEGF-Trap also differs markedly in different experimental tumours (Kanai et al, 1998;Asano et al, 1999;Rowe et al, 2000;Kim et al, 2002). With some of the earlier VEGFR2 kinase inhibitors, SU5416 and PTK787/ZK222584, slower growing tumours were found to be more inhibited by these agents than faster growing tumours (Fong et al, 1999;Wood et al, 2000).…”

mentioning

confidence: 99%

Antitumour efficacy of VEGFR2 tyrosine kinase inhibitor correlates with expression of VEGF and its receptor VEGFR2 in tumour models

et al. 2004

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During the development of indazolylpyrimidines as novel and potent inhibitors of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) tyrosine kinase, we observed that some human tumour xenografts are more sensitive to VEGFR2 kinase inhibitors than others. A better understanding of the basis for this differential response may help to identify a predictive marker that would greatly aid in the identification of a suitable patient population for treatment. One representative compound from the indazolylpyrimidine series is GW654652 that inhibited all three VEGFRs with similar potency. The inhibition of VEGFR2 kinase by GW654652 was about 150 to 48800 more potent than the inhibition of eight other kinases tested. GW654652 inhibited VEGFand bFGF-induced proliferation in endothelial cells with an IC 50 of 110 and 1980 nM, respectively, and has good pharmacokinetic profile in mouse and dog. We investigated the association between VEGF and VEGFR2 expression and the antitumour efficacy of GW654652, in various xenograft models. Statistically significant associations were observed between the antitumour efficacy of GW654652 in xenografts and VEGF protein (P ¼ 0.005) and VEGFR2 expression (P ¼ 0.041). The oral dose of GW654652 producing 50% inhibition of tumour growth (ED 50 ) decreased with increasing levels of VEGF (r ¼ À0.94); and, in contrast, the ED 50 increased with the increased expression of VEGFR2 (r ¼ 0.82). These results are consistent with the observed inverse correlation between VEGF and VEGFR2 expression in tumours. These findings support the hypothesis that VEGF and VEGFR2 expression by tumours may predict the therapeutic outcome of VEGFR kinase inhibitors.

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“…Inhibition of tumour growth in several tumour types using blocking antibodies against VEGF has been documented (13)(14)(15). Increases in the apoptotic fraction of tumour cells and a reduction in vascular density and permeability have been shown to result from neutralisation of VEGF or suppression of VEGF expression (16).…”

Section: Introductionmentioning

confidence: 99%

Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia

Barr

Bouchier‐Hayes²,

Harmey³

2008

Int J Oncol

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Abstract. Vascular endothelial growth factor (VEGF) is produced by most tumour types and stimulates the growth of new blood vessels in the tumour. The expansion of a solid tumour ultimately leads to the development of hypoxic regions, which increases VEGF production and further angiogenesis. In this study, we examined the role of VEGF in the survival of breast tumour cells under hypoxia. Murine 4T1 and human MDA-MB-231 tumour cells were cultured under normoxic and hypoxic growth conditions in the presence or absence of VEGF neutralising antibodies. Apoptosis was assessed in addition to changes in expression of the anti-and pro-apoptotic proteins, Bcl-2 and Bad, respectively. The effect of hypoxia on the novel VEGF receptor, NP1 (neuropilin-1) and the role of the PI3K (phosphatidylinositol-3-kinase) signalling pathway in response to VEGF were examined. VEGF blockade resulted in direct tumour cell apoptosis of both tumour cell lines under normoxia and hypoxia. While blocking VEGF resulted in a downregulation of hypoxia-induced Bcl-2 expression, there was a significant increase in the pro-apoptotic protein Bad relative to cells cultured under hypoxia alone. Both hypoxia and VEGF phosphorylated Akt. Neutralising antibodies to VEGF abrogated this effect, implicating the PI3K pathway in VEGF-mediated cell survival of mammary adenocarcinoma cells. This study demonstrates that VEGF acts as a survival factor not only for endothelial cells as previously thought, but also for some breast tumour cells, protecting them from apoptosis, particularly under hypoxic stress. The data presented provide an additional rationale for combining anti-VEGF strategies with conventional anti-cancer therapies such as chemotherapy and radiotherapy.

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Wide Spectrum of Antitumor Activity of a Neutralizing Monoclonal Antibody to Human Vascular Endothelial Growth Factor

Cited by 52 publications

References 30 publications

KDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells

KDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells

Antitumour efficacy of VEGFR2 tyrosine kinase inhibitor correlates with expression of VEGF and its receptor VEGFR2 in tumour models

Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia

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