Both Antiangiogenesis- and Angiogenesis-Independent Effects Are Responsible for Hepatocellular Carcinoma Growth Arrest by Tyrosine Kinase Inhibitor PTK787/ZK222584

Liu, Yuqing; Poon, Ronnie Tung‐Ping; Li, Qinyu; Kok, Tsz Wai; Lau, CK; Fan, Sheung Tat

doi:10.1158/0008-5472.can-04-3462

Cited by 100 publications

(68 citation statements)

References 38 publications

(45 reference statements)

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“…Consistent with this, preclinical evaluations suggest that the antitumor activity of sorafenib in HCC may be mediated by inhibition of angiogenesis (through inhibition of receptor tyrosine kinases), although direct effects on cell proliferation and survival cannot be excluded (Wilhelm et al, 2004;Liu et al, 2005). The promising preclinical activity of sorafenib has since been supported by clinical studies (Zhu, 2008).…”

Section: Therapeutic Targets In Hccmentioning

confidence: 86%

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The role of signaling pathways in the development and treatment of hepatocellular carcinoma

2010

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Section: Therapeutic Targets In Hccmentioning

confidence: 86%

“…In a preclinical study, it significantly reduced tumor volume and microvessel density in an HCC xenograft model (Liu et al, 2005). It also inhibited tumor cell proliferation and induced apoptosis in a dose-dependent manner (Liu et al, 2005).…”

Section: Therapeutic Targets In Hccmentioning

confidence: 99%

The role of signaling pathways in the development and treatment of hepatocellular carcinoma

2010

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“…Overexpression of VEGF has been documented in HCC [7] . A study has demonstrated that VEGF has an autocrine effect in stimulating cancer cell proliferation in HCC in addition to its angiogenic effect, further underscoring the importance of VEGF in HCC [19] . A strong VEGF expression was observed in the tissue of HCC and closely associated with tumor progression and metastasis [20] .…”

Section: Discussionmentioning

confidence: 98%

Impact of serum vascular endothelial growth factor on prognosis in patients with unresectable hepatocellular carcinoma after transarterial chemoembolization

Guo

Zhu

et al. 2012

Chin. J. Cancer Res.

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Objective: To investigate the expression level of serum vascular endothelial growth factor (VEGF) in patients with unresectable hepatocellular carcinoma (HCC) and its relationship with the clinicopathological characteristics, and to assess the impact of serum VEGF as a predictive factor for HCC prognosis during transarterial chemoembolization (TACE) treatments.Methods: Serum VEGF levels were measured using enzyme-linked immunosorbent assay (ELISA) in 60 random patients who underwent TACE or transarterial infusion (TAI) for unresectable HCC between May and September 2008 and 12 healthy volunteers were also involved in this study to serve as control. All patients' clinicopathological features were retrospectively analyzed. Serum VEGF levels were correlated with clinicopathological features of the HCC patients. The patients' survival rates were analyzed with Kaplan-Meier survival curves and compared by the log-rank test. The prognostic significance of serum VEGF levels and factors related to survival rate were evaluated by univariate and multivariate analysis.Results: The median serum VEGF level in the HCC patients was 285 pg/ml (range 14−1,207 pg/ml), significantly higher than that of healthy controls (P=0.021). The serum VEGF levels were significantly correlated with platelet counts (r=0.396, P=0.002) but not other clinicopathological features. Patients with serum VEGF level >285 pg/ml had worse overall survival compared with those with serum VEGF level <285 pg/ml (P=0.002). By multivariate analysis, the serum VEGF level was a significant prognostic factor.Conclusion: High serum VEGF levels may predict poor prognosis of HCC after TACE. This study highlights the importance of tumor biomarker as a prognostic predictor in TACE therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features.

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“…Based on our previous finding about the effects of PTK787 on human HCC cell lines (29) and study the study of Lee et al (41) showing that oral feeding of PTK787 at the dose of 50 mg/kg yielded 62.4 (F16.0) h Amol/L plasma exposure, we applied PTK787 at the concentration of Amol/L, to the tumor and endothelial cell lines, and found inhibitory effects on cell cycle progression and induction of cell apoptosis in both cell lines. We have also tested the effects of PTK787 on a human umbilical vascular endothelial cell and a mouse tumor-derived endothelial cell inhibited the motility of tumor cells through the membrane, and the suppression was further enhanced by the administration of PTK787.…”

Section: Discussionmentioning

confidence: 99%

High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: dual effects on cancer cell and angiogenesis

Yang

Poon

Liu

et al. 2006

Molecular Cancer Therapeutics

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The present study aimed to investigate the therapeutic efficacy of combining vascular endothelial growth factor (VEGF) receptor blockade using tyrosine kinase inhibitor PTK787 with hypoxia for the treatment of hepatocellular carcinoma (HCC). The in vivo effects of the treatments were determined in a rat orthotopic HCC model, in which hypoxia was generated by hepatic artery ligation (HAL). Compared with HAL alone, PTK787 combined with HAL significantly prolonged the animal survival, reduced the tumor size, induced more tumor tissue necrosis and apoptosis, and down-regulated the expression of von Willebrand factor. The mechanism was explored in vitro using murine HCC and endothelial cell lines, respectively. PTK787 combined with hypoxia decreased the expression of VEGF and VEGF receptors in both cell lines and suppressed the cell viability by induction of cell cycle arrest and promotion of apoptosis. Up-regulation of cleaved form caspase-9 and down-regulation of Bcl-2 and cyclin D1 were detected with the combined treatment. Hypoxia sensitized endothelial cells to the inhibitory effect of PTK787 on forming tubular-like structure. The motility of tumor cells was inhibited by hypoxia and the combined approach, with down-regulation of Rac1, Rho, and phosphorylated Akt expression. However, in the endothelial cells, the combined treatment inhibited the hypoxia-enhanced cell motility, with suppressed Rac1, Rho, and phosphorylated Akt expression. In conclusion, PTK787 combined with hypoxia achieved a better therapeutic efficacy than hypoxia alone through enhancing hypoxia-induced antitumor cell effect and preventing the activation of angiogenic process. [Mol Cancer Ther 2006;5(9):2261 -70]

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Both Antiangiogenesis- and Angiogenesis-Independent Effects Are Responsible for Hepatocellular Carcinoma Growth Arrest by Tyrosine Kinase Inhibitor PTK787/ZK222584

Abstract: Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis of hepatocellular carcinoma.

Cited by 100 publications

References 38 publications

The role of signaling pathways in the development and treatment of hepatocellular carcinoma

The role of signaling pathways in the development and treatment of hepatocellular carcinoma

Impact of serum vascular endothelial growth factor on prognosis in patients with unresectable hepatocellular carcinoma after transarterial chemoembolization

High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: dual effects on cancer cell and angiogenesis

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