Anticancer effects of ZD6474, a VEGF receptor tyrosine kinase inhibitor, in gefitinib (“Iressa”)‐sensitive and resistant xenograft models

Taguchi, Fumiko; Koh, Yasuhiro; Koizumi, Fumiaki; Tamura, Tomohide; Saijo, Nagahiro; Nishio, Kazuto

doi:10.1111/j.1349-7006.2004.tb03187.x

Cited by 60 publications

(41 citation statements)

References 11 publications

(15 reference statements)

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“…Treatment with vandetanib resulted in a dose-dependent decrease in the proportion of proliferating cells in the gefitinib-sensitive tumors but not in the gefitinib-resistant xenografts (169). No significant increases in apoptosis were observed in either tumor type (169). In a similar approach, the efficacy of vandetanib has been evaluated in human GEO colon cancer xenografts with acquired resistance to EGFR inhibitors (160).…”

Section: Combined Vegf and Egfr Inhibition: Why Join Forces?mentioning

confidence: 98%

“…Vandetanib has also been evaluated in EGFR inhibitorsensitive and -resistant cell lines (160, 169). Taguchi et al (169) examined the antitumor activity of vandetanib in the gefitinib-sensitive lung adenocarcinoma cell line PC-9 and a gefitinib-resistant variant, PC-9/ZD. Treatment with vandetanib resulted in a dose-dependent decrease in the proportion of proliferating cells in the gefitinib-sensitive tumors but not in the gefitinib-resistant xenografts (169).…”

Section: Combined Vegf and Egfr Inhibition: Why Join Forces?mentioning

confidence: 99%

“…Taguchi et al (169) examined the antitumor activity of vandetanib in the gefitinib-sensitive lung adenocarcinoma cell line PC-9 and a gefitinib-resistant variant, PC-9/ZD. Treatment with vandetanib resulted in a dose-dependent decrease in the proportion of proliferating cells in the gefitinib-sensitive tumors but not in the gefitinib-resistant xenografts (169). No significant increases in apoptosis were observed in either tumor type (169).…”

Section: Combined Vegf and Egfr Inhibition: Why Join Forces?mentioning

confidence: 99%

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The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents

Tabernero

2007

Molecular Cancer Research

380

266

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Section: Combined Vegf and Egfr Inhibition: Why Join Forces?mentioning

confidence: 98%

Section: Combined Vegf and Egfr Inhibition: Why Join Forces?mentioning

confidence: 99%

Section: Combined Vegf and Egfr Inhibition: Why Join Forces?mentioning

confidence: 99%

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The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents

Tabernero

2007

Molecular Cancer Research

380

266

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“…The vandetanib IC 50 for the PC-9 lung cancer cell line, which is sensitive to EGFR inhibitors, was reported earlier to be 0.14 mM (Taguchi et al, 2004). Compared with this data, TKKK cells were also sensitive to vandetanib (IC 50 : 0.22 mM), TGBC24TKB was moderately resistant (IC 50 : 4.5 mM), and OZ and HuCCT1 cells (IC 50 s of 12.2 and 10 mM, respectively) were considered refractory.…”

Section: Anti-proliferative Effect Of Vandetanib In Vitromentioning

confidence: 99%

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma

Yoshikawa

Ojima²,

Kokubu³

et al. 2009

Br J Cancer

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Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses X12.5 mg kg À1 day À1 (Po0.05), but higher doses (50 mg kg À1 day À1 , Po0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg À1 day À1 ) also significantly (P ¼ 0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma.

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“…[10][11][12][13] We demonstrated previously the evidence suggesting that ZD6474 inhibits angiogenesis and tumor growth by targeting EGFR. 14,15 In our present study, we tested ZD6474 for an inhibitory effect on tumor growth and intraperitoneal dissemination, and for improvement of survival in a newly established, highly metastatic orthotopic gastric tumor model in vivo. In addition, we also identified putative biomarkers to monitor the effects of ZD6474 treatment using gene expression profiling.…”

mentioning

confidence: 99%

ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model

Arao

Yanagihara²,

Takigahira³

et al. 2006

Int. J. Cancer

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Angiogenesis inhibitors have been used to treat some cancers, but the therapeutic potential of these agents for gastric cancer has remained unclear. To investigate their therapeutic potential, we examined the effect of ZD6474, an agent that selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2; KDR) tyrosine kinase and epidermal growth factor receptor (EGFR) tyrosine kinase, in a highly metastatic orthotopic model using an undifferentiated gastric cancer cell line, 58As1. ZD6474 (100 mg/ kg/day, p.o., 2 weeks) significantly inhibited tumor growth (p < 0.05 vs. control) and reduced tumor dissemination into the peritoneal cavity (p < 0.05 vs. control). In addition, to identify putative tumor biomarkers that would reflect the effects of ZD6474 treatment in clinical settings, we examined the gene expression profiles of implanted gastric tumors treated with ZD6474 in vivo. Twentyeight candidate genes were identified, including IGFBP-3, ADM, ANGPTL4, PLOD2, DSIPI, NDRG1, ENO2, HIG2 and BNIP3L, which are known to be hypoxia-inducible genes. These genes and gene products may be useful biomarkers for monitoring the effects of ZD6474 treatment. ZD6474 also improved the survival of mice with implanted another undifferentiated gastric cancer cell line, 44As3. In conclusion, our results suggest that ZD6474 may have clinical activity against gastric cancer, particularly undifferentiated gastric cancer with peritoneal dissemination. We also identified putative biomarkers for monitoring the pharmacodynamic effects of ZD6474 by gene expression profiling. ' 2005 Wiley-Liss, Inc.Key words: ZD6474; gastric cancer; intraperitoneal dissemination; VEGF; oligonucleotide microarray Various anti-cancer agents have been examined for efficacy against gastric cancer over the past two decades, but the median survival time of patients remains around 7 months, 1,2 and the prognosis of gastric cancer patients remains poor. Peritoneal dissemination is common in patients with unresectable gastrointestinal cancer, and many suffer from peritoneal carcinomatosis in the terminal stage. Because undifferentiated gastric cancer is particularly invasive and often accompanied by peritoneal dissemination, 3 a new treatment strategy is needed.Vascular endothelial growth factor (VEGF) is a key mediator of tumor growth and is known to have multiple functions in angiogenesis, vascular permeability, and the regulation of endothelial cell proliferation and migration. 4-6 VEGF receptors (VEGFR) are activated by ligand stimulation with VEGF and commonly expressed in vascular endothelial cells. VEGFR-2 (KDR/Flk-1) is thought to be important for angiogenesis. 7 Because the VEGF-VEGFR system plays a key role in angiogenesis and tumor growth in vivo, the therapeutic potential of many agents targeting this system is being investigated. 8 A recent study has shown that a combination of monoclonal antibody against VEGF and chemotherapy produces a clinically meaningful survival benefit for patients with metastatic colorectal cancer, 5 and these result...

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Anticancer effects of ZD6474, a VEGF receptor tyrosine kinase inhibitor, in gefitinib (“Iressa”)‐sensitive and resistant xenograft models

Cited by 60 publications

References 11 publications

The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents

The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma

ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model

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