2000 Fiscal Year Final Research Report Summary
Molecular cancer therapy based on the pathological analysis of the pancreatic cancer
| Project/Area Number |
10470258
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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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 | KYOTO UNIVERSITY |
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Principal Investigator |
HOSOTANI Ryo Graduate School of Medicine, KYOTO UNIVERSITY Associate Professor, 医学研究科, 助教授 (00139908)
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| Co-Investigator(Kenkyū-buntansha) |
SASAI Keishi Graduate School of Medicine, KYOTO UNIVERSITY Associate Professor, 医学研究科, 助教授 (20225858)
FUJII Nobutaka Graduate School of Pharmaceutical Science, KYOTO UNIVERSITY Professor, 薬学研究科, 教授 (60109014)
IMAMURA Masayuki Graduate School of Medicine, KYOTO UNIVERSITY, Professor, 医学研究科, 教授 (00108995)
KOGIRE Masafumi Graduate School of Medicine, KYOTO UNIVERSITY Assistant Professor, 医学研究科, 助手 (60283595)
DOI Ryuichiro Graduate School of Medicine, KYOTO UNIVERSITY Instructor, 医学研究科, 講師 (20301236)
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| Project Period (FY) |
1998 – 2000
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| Keywords | Apoptosis / Bcl-X gene / p16 / Signal transduction / integrin αV β3 / Pancreatic cancer |
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| Research Abstract |
1.Signal transduction of apoptosis and pancreatic cancer therapy
Expression analysis of the pancreatic cancer tissue demonstrated over-expression of Bcl2-related proteins, particularly Bcl-X.In pancreatic cancer cells, i) cellular susceptibility to radiation-induced apoptosis was correlated with Bax/Bcl-2 ratio, ii) exogenous CDK inhibitor induced apoptosis with the rise in Bax/Bcl-2 ratio, and iii) Bcl-X expression was induced in radiation-resistant cells. Bcl-X antisense treatment in cancer cells caused sequence-specific transcriptional inhibition and subsequent augmentation of radiation-induced apoptosis.
2.Development of new anti-cancer agents based on gene abnormalities
A new synthetic retinoid, TAC-101, showed a potent growth inhibition of pancreatic cancer cells. Induction of endogenous CDK inhibitor, p21 and p27, was involved in the mechanism. We have synthesized p16-peptide with antennapedia carrier peptide. The peptide penetrated into the cells and showed significant growth inhi
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bition, which was associated with G1 arrest of the cell cycle. p16 treatment in mice demonstrated a marked inhibition of tumor growth in subcutaneous tumor model and significant survival benefit in peritoneal dissemination model. The results suggest the possible strategy for the development of new anti-cancer agents based on the gene abnormalities.
3.Pancreatic cancer therapy for tumor dormancy
Expression analysis of the cancer tissue showed strong expression of VEGF and PD-ECGF in cancer cells and significant correlation of the expression of these angiogenic factors with tumor angiogenesis. When chemotaxis of the angiogenic endothelial cells were concerned, SDF-1 gene was expressed in the cancer stromal cells and its receptor CXCR-4 was expressed in cancer cells and endothelial cells. This SDF/CXCR-4 system was involved in the mechanism of migration of pancreatic cancer cells and endothelial cells. We have newly synthesized cyclic RGD peptide with E-alkane bond which is specific for integrin αV β3. This RGD peptide showed potent inhibitory effect on both attachment and growth of endothelial cells. In subcutaneous tumor model, RGD peptide treatment induced tumor dormancy, when the treatment started before tumor growth depends on angiogenesis. Less
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