2004 Fiscal Year Final Research Report Summary
Establishment of specific immunotherapy by activation of innate immunity
| Project/Area Number |
15591422
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Fukushima Medical University |
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Principal Investigator |
TERASHIMA Masanori Fukushima Medical University, School of Medicine, Department of Surgely, Associate Professor, 医学部, 助教授 (40197794)
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| Co-Investigator(Kenkyū-buntansha) |
GOTOH Mitsikazu Fukushima Medical University, School of Medicine, Department of Surgery, Professor, 医学部, 教授 (50162160)
KOGURE Michihiko Fukushima Medical University, School of Medicine, Department of Surgery, Assistant Professor, 医学部, 講師 (90264548)
HOSHINO Yutaka Fukushima Medical University, School of Medicine, Department of Surgery, Instructor, 医学部, 助手 (30295414)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Cancer / Nucleotide / Surgery / Drug response / Cancer chemotherapy |
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| Research Abstract |
In order to establish an efficient combination therapy with chemotherapy and immunotherapy, selection of chemotherapeutic agents those effectively induce apoptosis on tumor cells and have less effect to systemic immunological activity. We investigated the growth inhibitory activity of anticancer agent on human peripheral blood mononudear cells (PBMC), apoptosis inducing activity on gastric cancer cells and expression of toll-like receptor (TLR)-4 mRNA on DCs by parlituel (1XL) and docetaxel (TXT). We further compared the cytotoxidty of cytothdc T lymphocytes (CTLs) induced by DCs pulsed with tumor lysate and apoptotic cells induced by TXT. PBMC were collected from healthy volunteers and cultured in RPM1640 with 10% PCS Anticanoer agents were added at concentrations of peak plasma concentration (PPC), 0.1xPP and 10xPPC concomitant with PHA Proliferating activity of PBMC was determined by measuring intracellular Al? levels. Apoptosis was evaluated by 1UNNEL assay. Immature DCs were obtai
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ned by culturing PBMCs in serum-free medium (AIM V) with interieukin-4 (IL-4 ; 5Ong/ml) and granulocyte-maaophage stimulating factor (GM-SP 5Ong/m1) for 5 days. Then DCs were pulsed with tumor cell lysate obtained from gastric cancer cells MKN45 or apoptotic MKN45 cells induced by TXT for 12hr and further cultured for 30hr following addition of OK-432 (0.1 KE/ml). CIL activity was determined by LDH-releasing assay. Although most of anticancer agents demonstrated the suppression activity on proliferation of PBMC in a dose dependent manner, TXT, doxifluridine and irinobecane did not show the suppressive activity on PBMC even in the highest drug concentration. About 60% of MKN45 cells demonstrated apoptosis after 24hr. and 48hr treatment of both 1XL and TXT. Expression of TLR-4 mRNA in iDCs was up-regulated by TXT, not by TXT, peaked at 2 hr after treatment at a concentration 1×10-8M Clis induced by DCs pulsed with tumor lysate and apoptotic cells showed similar killing activity to tarwt cells. These results suggest that TXT appears to be a optimal anticancer agent for a combination therapy with chemotherapy and tumor specific immunotherapy using dendritic cells in gastric cancer.
We then planed a prospective clinical Phase I/II trial using a combination chemotherapy of TXT and 5 v-DFUR followed by intra-tumoral immature DC injection in patients with gastric cancer. So far, three patients were included and the analysis of immunological and clinicopathblogic parameters are now underway. Less
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Research Products
(9 results)
