Combination therapy with tumor-lysate pulsed dendritic cells and antiangiogenic drug TNP-470 for mouse pancreatic cancer.
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/TL- (DCs without TL), DC/TL+ (DCs pulsed with TL), TNP (TNP-470 alone), DC/TL-TNP (DC/TL- plus TNP-470) and DC/TL+TNP (DC/TL+ 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/TL+TNP group. There were no significant differences in apoptosis among the 6 groups except DC/TL+. The number of infiltrating CD4+ cells in the DC/TL+ 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/TL+. 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.
Miyazaki
Junichi
J
Second Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
Tsuzuki
Yoshikazu
Y
Matsuzaki
Koji
K
Hokari
Ryota
R
Okada
Yoshikiyo
Y
Kawaguchi
Atsushi
A
Nagao
Shigeaki
S
Itoh
Kazuro
K
Miura
Soichiro
S
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002455:Cell Division; D002470:Cell Survival; D003131:Combined Modality Therapy; D003510:Cyclohexanes; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D007167:Immunotherapy; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D051379:Mice; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D012717:Sesquiterpenes / Q000627:therapeutic use*; D013154:Spleen / Q000276:immunology
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol