Antivascular Therapy for Orthotopic Human Ovarian Carcinoma through Blockade of the Vascular Endothelial Growth Factor and Epidermal Growth Factor Receptors

Abstract

Purpose: We determined whether the administration of the tyrosine kinase inhibitor, AEE788, which targets the epidermal growth factor receptor and the vascular endothelial growth factor receptor, alone or in combination with paclitaxel, can inhibit progressive growth of human ovarian carcinoma in the peritoneal cavity of female nude mice. Experimental Design:Western blot analysis and immunohistochemical analysis identified the optimal dose and schedule of AEE788 therapy. In several different experiments, paclitaxelsensitive and paclitaxel-resistant human ovarian carcinoma cells were injected into the peritoneal cavity of nude mice. Seven days later, treatment with saline (control), AEE788 alone, paclitaxel alone, or a combination of AEE788 and paclitaxel began and continued for 45 days when the mice were necropsied. In independent survival experiments, the mice were necropsied when they became moribund. Results: Oral administration of AEE788 inhibited phosphorylation of the epidermal growth factor receptor and vascular endothelial growth factor receptor for up to 48 hours. Treatment with AEE788 plus paclitaxel significantly reduced tumor weight and increased survival of mice implanted with paclitaxel-sensitive cell lines compared with control mice or mice treated with AEE788 alone or paclitaxel alone. In mice implanted with paclitaxel-resistant cells, the combination therapy also significantly reduced tumor weight but did not prolong survival.The combination therapy induced apoptosis of both tumor cells and tumor-associated endothelial cells. Conclusions: The administration of AEE788 and paclitaxel inhibits the progression of human ovarian carcinoma in the peritoneal cavity of female nude mice, in part, by inducing apoptosis of tumor-associated endothelial cells.

Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models

“…AEE788, a dual tyrosine kinase inhibitor of both EGFR and VEGFR, now provides an avenue to investigate the effect of simultaneous blockade of EGFR and VEGFR (27)(28)(29)(30)(31)(32)(33)(34)(35) in cancer cells. We hypothesized that dual inhibition of both targets using AEE788 in prostate cancer will lead to improved tumor control when combined with radiation.…”

Vascular endothelial growth factor (VEGF) pathway as a therapeutic target in gynecologic malignancies

“…Teicher and colleagues [51] were the first to show synergistic activity between these agents for treatment of tumors in mice. Similarly, in multiple studies, we and others have noted enhanced anti-tumor activity when a cytotoxic agent is combined with an anti-angiogenic agent [28,[52][53][54][55]. Based on these preclinical data and clinical data from other cancer sites such as colorectal cancer [43] demonstrating improved response rates of antiangiogenic agents with a traditional cytotoxic agent, such combinations are also being evaluated in gynecologic malignancies.…”

“…The prosurvival effects of VEGF/VEGFR-2 are mediated by the PI3 kinase-Akt pathway [25]. Recent studies indicate that VEGF receptors are also expressed by some tumor cells and may represent an additional target [6,[26][27][28].…”

“…In an ovarian cancer nude mice model, single agent ZD6474 had a significant anti-tumor effect [67]. Single agent AEE788 or paclitaxel had an intermediate effect when compared to controls and combination therapy [28]. Combination therapy with AEE788 and paclitaxel greatly reduced tumor burden when compared to control mice.…”

Hypoxia modulation and radiosensitization by the novel dual EGFR and VEGFR inhibitor AEE788 in spontaneous and related allograft tumor models

“…However, we could directly determine a cellular response on the level of tumor cell proliferation and apoptosis and changes at the level of the tumor vasculature. Furthermore, other groups showed that the activity of these receptors is specifically inhibited upon treatment of AEE788, applying even lower AEE788 treatment regimens (31,33,34,38).…”