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

International Journal of Cancer - Tập 117 Số 3 - Trang 499-505 - 2005
Jun‐ichi Miyazaki1, Yoshikazu Tsuzuki, Koji Matsuzaki, Ryota Hokari, Yoshikiyo Okada, Atsushi Kawaguchi, Shigeaki Nagao, Kazuro Itoh, Soichiro Miura
1Second Department of Internal Medicine, National Defense Medical College, Saitama, Japan

Tóm tắt

AbstractMost 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. © 2005 Wiley‐Liss, Inc.

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Tài liệu tham khảo

10.1023/A:1008353523865

10.1023/A:1006383831045

Nestle FO, 1997, Human sunlight‐induced basal‐cell‐carcinoma‐associated dendritic cells are deficient in T cell co‐stimulatory molecules and are impaired as antigen‐presenting cells, Am J Pathol, 150, 641

10.1002/(SICI)1097-0215(19970807)72:4<619::AID-IJC12>3.0.CO;2-6

10.1038/nm0398-328

10.1385/IJGC:32:1:1

10.1002/(SICI)1097-0045(19990101)38:1<73::AID-PROS9>3.0.CO;2-V

10.1038/32588

10.1084/jem.183.1.7

Macatonia SE, 1995, Dendritic cells produce IL‐12 and direct the development of Th1 cells from naive CD4+ T cells, J Immunol, 154, 5071, 10.4049/jimmunol.154.10.5071

10.1084/jem.183.1.87

10.1074/jbc.272.26.16351

10.1038/nm0295-149

10.1056/NEJM197111182852108

10.1073/pnas.94.3.861

Senger DR, 1986, A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines, Cancer Res, 46, 5629

Himelstein BP, 1994, Metalloproteinases in tumor progression: the contribution of MMP‐9, Invasion Metastasis, 14, 246

10.1002/(SICI)1096-911X(199812)31:6<471::AID-MPO2>3.0.CO;2-M

10.1038/348555a0

10.1016/0092-8674(94)90200-3

10.1016/S0092-8674(00)81848-6

Logothetis CJ, 2001, Phase I trial of the angiogenesis inhibitor TNP‐470 for progressive androgen‐independent prostate cancer, Clin Cancer Res, 7, 1198

Bhargava P, 1999, A phase I and pharmacokinetic study of TNP‐470 administered weekly to patients with advanced cancer, Clin Cancer Res, 5, 1989

Yu B, 2003, Effective combination of chemotherapy and dendritic cell administration for the treatment of advanced‐stage experimental breast cancer, Clin Cancer Res, 9, 285

10.1002/1097-0215(20011215)94:6<825::AID-IJC1545>3.0.CO;2-5

Browder T, 2000, Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug‐resistant cancer, Cancer Res, 60, 1878

Mysliwski A, 2000, Synergistic effect of the angiogenesis inhibitor TNP‐470 and tumor necrosis factor (TNF) on Bomirski Ab melanoma in hamsters, Anticancer Res, 20, 4643

10.1038/37126

Corbett TH, 1984, Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice, Cancer Res, 44, 717

10.1038/sj.bjc.6600026

Inoue K, 2002, Frequent administration of angiogenesis inhibitor TNP‐470 (AGM‐1470) at an optimal biological dose inhibits tumor growth and metastasis of metastatic human transitional cell carcinoma in the urinary bladder, Clin Cancer Res, 8, 2389

10.1038/labinvest.3780357

Tsuzuki Y, 2000, Vascular endothelial growth factor (VEGF) modulation by targeting hypoxia‐inducible factor‐1α→hypoxia response element→VEGF cascade differentially regulates vascular response and growth rate in tumors, Cancer Res, 60, 6248

Schmidt T, 2003, Intratumoral immunization with tumor RNA‐pulsed dendritic cells confers antitumor immunity in a C57BL/6 pancreatic murine tumor model, Cancer Res, 63, 8962

10.1073/pnas.95.16.9482

10.1073/pnas.96.6.2982

10.1084/jem.191.5.795

10.1073/pnas.97.26.14608

10.1074/jbc.M202959200

Sedlakova O, 1999, Angiogenesis inhibitor TNP‐470: cytotoxic effects on human neoplastic cell lines, Neoplasma, 46, 283

10.1016/0016-5085(95)90703-3

10.1007/BF01972729

Gabrilovich DI, 1999, Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function, Clin Cancer Res, 5, 2963

10.1111/j.1349-7006.1998.tb00655.x

Klement G, 2002, Differences in therapeutic indexes of combination metronomic chemotherapy and an anti‐VEGFR‐2 antibody in multidrug‐resistant human breast cancer xenografts, Clin Cancer Res, 8, 221

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International Journal of Cancer

Tập 117 Số 3

499-505

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