Inhibition of angiogenesis and growth of human nerve-sheath tumors by AGM-1470

Abstract

The effectiveness of AGM-1470, a potent, fungal-derived inhibitor of angiogenesis, in suppressing the neovascularization and growth of human Schwann cell tumors was tested in six schwannomas, seven neurofibromas, and one neurofibrosarcoma. Tumor fragments from surgical specimens were implanted into the subrenal capsule of 348 nude mice (nu/nu). Seven days after implantation, the tumors were measured and vascularity was graded. The animals were then randomly assigned to one of two groups, to receive either saline (control group) or systemic AGM-1470 treatment. After 2 to 6 weeks of treatment, tumor size and degree of vascularity were recorded. In the six different schwannomas implanted into 138 mice, the average vascular grade in the control group after 2 weeks of treatment increased from 2.2 to 3.2 (+1.0), while in the AGM-1470-treated group it decreased from 2.2 to 1.7 (-0.5) (p < 0.01). In the seven different neurofibromas implanted into 158 mice, the change in the average vascular grade in control and AGM-1470-treated animals was +0.5 and -1.0, respectively (p < 0.01). In the one neurofibrosarcoma implanted into 52 mice, the change in average vascular grade in each group during the 6-week treatment period was +1.9 and -1.0, respectively (p < 0.01). Neurofibrosarcoma growth after 6 weeks of AGM-1470 treatment was only 8.5% of the growth found in the control animals (p < 0.01). This study determined that AGM-1470 is effective in inhibiting angiogenesis and the growth of human nerve-sheath tumors.

Combined effects of an angiogenesis inhibitor (TNP-470) and hyperthermia

“…Although inhibition of angiogenesis by TNP-470 has been demonstrated by a vascular grading system in human nerve sheath tumours (Takamiya et al, 1993), this study first showed that TNP-470 inhibited tumour angiogenesis in vivo quantitatively. This analysis system of tumour angiogenesis after hyperthermia seems a good model to study angiogenesis of murine tumour vasculature in vivo because hyperthermia at a high heat dose inevitably destroys murine tumour vasculature followed by angiogenesis.…”

The antiangiogenic agent TNP-470 requires p53 and p21 CIP/WAF for endothelial cell growth arrest

“…TNP-470, a synthetic derivative of fumagillin, was shown to posses potent antiangiogenic activity and low toxicity in animal studies (5,6). Based on promising preclinical studies showing that TNP-470 inhibits the growth of solid tumors and prevents their metastasis (7)(8)(9)(10)(11)(12), this antiangiogenic compound was one of the earliest to enter antitumor clinical trials (13).…”

Basic Fibroblast Growth Factor Infusion Increases Tumour Vascularity, Blood Flow and Chemotherapy Uptake

“…Thus a bFGF-induced increase in tumour vascularity may stimulate tumour growth (30,31) or metastasis (32,33), particularly in the 38% of human colorectal carcinomas reported to have bFGF receptors (34). The possible bene ts of angiogenesis-enhanced chemotherapy delivery need to be balanced against the risks of accelerated tumour growth and metastasis.…”