Antitumor Effect of a Neutralizing Antibody to Vascular Endothelial Growth Factor on Liver Metastasis of Endocrine Neoplasm

Abstract

Distant metastasis of gastrointestinal endocrine neoplasm is resistant to currently available treatments. Because hematogenic metastasis is dominant, anti-angiogenic drugs are expected to be a novel therapy for this neoplasm. In the present study, the therapeutic effect of vascular endothelial growth factor neutralizing antibody (VEGFAb) on liver metastasis of an endocrine neoplasm was investigated experimentally. Cecal transplantation into nude mice of small pieces of EN-1, a xenotransplanted human intestinal endocrine neoplasm, resulted in liver metastasis. A treated group (n= = = =19) received 100 µ µ µ µg/mouse of VEGFAb intraperitoneally on alternate days from day 10 2) Endocrine cell carcinoma is an endocrine tumor with high malignant potential, and in principle is more aggressive than carcinoma.We established a xenotransplanted human intestinal endocrine neoplasm, EN-1, from a duodenal carcinoid tumor. It retains the immunohistochemical and ultrastructural features of the endocrine tumor. A liver metastatic model of EN-1 was produced by cecal transplantion into nude mice.Currently available therapeutic options for endocrine tumor include surgery, chemotherapy, radiotherapy, and hormonal manipulation. However, the therapeutic effects of those modalities on distant metastasis of the gastrointestinal endocrine tumor are limited. 3)Endocrine neoplasms frequently show hematogenic metastasis. This suggests that anti-angiogenic drugs may represent a novel therapy for this neoplasm, because angiogenic factors reportedly play an important role in the hematogenic metastasis of human malignancies. We have previously reported the therapeutic effect of an angiogenesis inhibitor on the liver metastasis of human gastrointestinal malignancies. [4][5][6] In the present study, the therapeutic effect of vascular endothelial cell growth factor neutralizing monoclonal antibody (VEGFAb) on the liver metastasis of EN-1 was investigated by using a liver metastatic model, with the aim of developing a novel therapy for endocrine neoplasm. MATERIALS AND METHODS EN-1 (human endocrine neoplasm)In January 1990, a duodenal lesion was aseptically resected from a 68-yearold Japanese woman who had liver metastases arising from a duodenal atypical carcinoid. The resected specimen was aseptically transplanted into nude mice, and a cell line was established in vitro and designated CT-nu-1. The carcinoid tumor was re-established in vivo by subcutaneous injection of CT-nu-1 cells into BALB/c nude mice and designated EN-1. EN-1 has been maintained by subcutaneous passage for about 2 years. Animals Male BALB/c nu/nu mice were obtained from

The Development and Characterization of a Human Midgut Carcinoid Cell Line

“…Midgut carcinoid models that rely solely on maintaining a transplantable tumor in vivo are limited by their inability to grow in the controlled setting of tissue culture (17). The ability of our cell line to form colonies in soft agar offers indirect (in vitro) proof of its tumorigenicity.…”

Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment

“…Treatment with a neutralising antibody to VEGF in mice with a duodenal carcinoid resulted in decreased tumour size and inhibition of liver metastasis (Konno et al 1998). Furthermore, a MAB that blocks the VEGFA ligand and an antibody blocking the VEGF receptor subtype 2 have been tested in the RIP-Tag2 mouse model of insulinoma with consistent antiangiogenic effects on microvessel density, endothelial cell proliferation and anti-tumour activity with increased apoptosis (Casanovas et al 2005, Sennino et al 2012.…”

Somatostatin analogs for the treatment of neuroendocrine tumors

“…In a xenograft model of a human carcinoid, treatment with bevacizumab, an anti-VEGF monoclonal antibody, was found to inhibit tumor growth and metastases [49]. The activity of bevacizumab, or pegylated IFN-α-2b, as monotherapy, followed by a combination of the two agents in patients with advanced carcinoid tumors that previously were receiving octreotide, was examined in a randomized phase II study [50].…”