Combination therapy with tumor‐lysate pulsed dendritic cells and antiangiogenic drug TNP‐470 for mouse pancreatic cancer

Abstract

Most cases of pancreatic cancer are inoperable when diagnosed. Since immunotherapy and antiangiogenic therapy have been reported to be promising for pancreatic cancer, we examined whether the combination of immunotherapy with dendritic cells (DCs) and the antiangiogenic drug TNP-470 induces tumor regression. Syngeneic mouse pancreatic adenocarcinoma cells were orthotopically inoculated into C57/BL6 mice. DCs with or without tumor lysate (TL) were administered i.p. at 4 and 5 weeks. TNP-470 was injected s.c. into tumor-bearing mice every other day from 4 weeks to 6 weeks. We compared anticancer effects in 6 groups: NT (no treatment), DC/TL2 (DCs without TL), DC/TL1 (DCs pulsed with TL), TNP (TNP-470 alone), DC/TL-TNP (DC/TL2 plus TNP-470) and DC/TL1TNP (DC/TL1 plus TNP-470). We measured tumor volume, mean vascular density (MVD) and vessel diameter by FITC-dextran using an intravital microscope; degrees of proliferation and apoptosis of cancer cells by PCNA and TUNEL; infiltrating lymphocytes and expression levels of VEGF and MMP-9 by immunohistochemistry and immunoblotting. Tumor volume and MVD were significantly suppressed in the treatment groups with prolonged survival rate, especially in the DC/TL1TNP group. There were no significant differences in apoptosis among the 6 groups except DC/TL1. The number of infiltrating CD4 1 cells in the DC/TL1 group was higher than that in the NT group. VEGF expression was significantly suppressed in the treatment groups containing TNP-470, and MMP-9 was also suppressed in the groups containing DC/TL1. Our data suggested that TL-pulsed DCs combined with TNP-470 induced regression of mouse pancreatic cancer, possibly through induction of immune responses and suppression of angiogenesis. ' 2005 Wiley-Liss, Inc.

Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer

“…TNP-470 [O -(chloroacetyl-carbamoyl) fumagillol, AGM-1470] was initially derived from fumagillin and has potent antiangiogenic effects in many tumors (10, 11, 28 -31). TNP-470 reduces tumor size in pancreatic (29,32), bladder (33), and cervical and prostate cancer (34). However, few studies have examined the intracellular pathways that mediate the endothelial effects of TNP-470.…”

Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model

“…Male C57BL/6 mice, 4-5 weeks of age and maintained on standard laboratory chow (Oriental Yeast, Tokyo, Japan), were used for the study. Preparation of cells and the tumor inoculation were performed according to our previous report (32,33). Briefly, under pentobarbital anesthesia, a small left lateral laparotomy was performed and a pellet containing 4x10 5 cells in growth factor-reduced Matrigel (BD Biosciences, Bedford, MA) was injected into the pancreas.…”

“…We previously established a pancreas cancer model by inoculation of pancreas cancer cells into pancreas tissue, which is more appropriate for studying pancreas cancer immunology than using subcutaneous tumors (32). Since surface expression of adhesion molecules on inflammatory cells regulates organ-specific recruitment, cancer immunity against a subcutaneous tumor may differ from that of a tumor in the pancreas, where gut-tropic infiltrating cells mainly play a role.…”

Effects of Intratumoral Injection of CCL2 on Monocyte–Endothelial Cell Interactions in Mouse Pancreatic Cancer

“…Male C57BL/6 mice, 4–5 weeks of age maintained on standard laboratory chow (Oriental Yeast, Tokyo, Japan) were used for the study. Preparation of cells and the tumor inoculation were according to our previous report [ 27 ]. Briefly, under pentobarbital anesthesia, a small left lateral laparotomy was performed and a pellet containing 4 × 10 5 cells in growth factor‐reduced Matrigel (BD Biosciences, Bedford, MA) was injected into the pancreas.…”