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

Abstract

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...

In vivo and Microarray Analysis of Rexinoid-Responsive Anaplastic Thyroid Carcinoma

“…* Genes that have no designated gene symbol. endothelial growth factor receptor inhibition which resulted in decreased vascularity and increased hypoxia (27). However, a study by Ito and colleagues showed that a mouse that overexpressed ANGPTL4 showed inhibition of colorectal xenograft tumor growth and decreased vascularity within the tumors (26).…”

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

“…Oligonucleotide microarray study and microarray analysis A microarray procedure was performed as described previously (Arao et al, 2006). In brief, total RNA extracts were collected from A549 cells transfected with ATF4 siRNA (50 or 0.3 nM) or control siRNA (50 or 0.3 nM) in duplicate.…”

Antitumor Effect of SN-38–Releasing Polymeric Micelles, NK012, on Spontaneous Peritoneal Metastases from Orthotopic Gastric Cancer in Mice Compared with Irinotecan

“…In this study, we used mouse models with orthotopically transplanted human scirrhous gastric cancer cells showing spontaneously progressing peritoneal dissemination, which we reported previously (18,19,21). These models can imitate more realistically the progressing mode of human peritoneal dissemination of gastric cancer than conventional experimental models directly transplanted with cancer cells i.p.…”

“…44As3 and 58As1m were previously reported as human signet-ring cell gastric cancer cell lines that spontaneously metastasize to the peritoneal cavity and produce large volumes of bloody ascites after orthotopic implantion in the gastric wall (18)(19)(20)(21). Here, 44As3 and 58As1m cells were transfected with a complex of 4 Ag of pEGF-PLuc plasmid DNA (Clontech) and 24 AL of GeneJammer reagent (Stratagene; Cloning Systems) in accordance with the manufacturer's instructions.…”

“…Ambient light was controlled to provide regular cycles of 12 h of light and 12 h of darkness. A total of 1 Â 10 6 cells of 44As3Luc or 58As1Luc were inoculated into the gastric wall of each mouse after laparotomy, as described previously (18)(19)(20)(21). In vivo photon counting analysis was conducted on a cryogenically cooled IVIS system using Living Image acquisition and analysis software (Xenogen).…”