2003 Fiscal Year Final Research Report Summary
Establishment of a novel mouse model for studying prostate cancer metastasis to human bone and new therapeutic strategies.
| Project/Area Number |
13557136
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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 | 展開研究 |
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| Research Field |
Urology
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| Research Institution | KEIO UNIVERSITY |
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Principal Investigator |
MURAI Masaru Keio University, School of Medicine, Professor, 医学部, 教授 (90101956)
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| Co-Investigator(Kenkyū-buntansha) |
YAMADA Taketo Keio University, School of Medicine, Assistant professor, 医学部, 専任講師 (60230463)
OYA Mototsugu Keio University, School of Medicine, Assistant professor, 医学部, 専任講師 (00213885)
NAKASHIMA Jun Keio University, School of Medicine, Assistant professor, 医学部, 専任講師 (10167546)
ITO Fumio Takeda Chemical Industries Ltd., Medicinal Chemistry Research Laboratories, Senior Scientist, 創薬化学研究所, 研究職
HOZUMI Nobumichi Tokyo University of Science, Research Institute for Biological Science, Professor, 生命科学研究所, 教授 (60051744)
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| Project Period (FY) |
2001 – 2003
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| Keywords | prostate cancer / bone metastases / angiogenesis / bcl-2 / NFkappaB |
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| Research Abstract |
Tumors arising from the prostate possess a special propensity to metastasize to bone. We have carried out a series of experiments aimed at inhibition of human angiogenesis for the development of a therapeutic strategy to bone metastasis using HuBone-NOD-SCID mice. Tumor cells produce angiogenetic factors such as VECF and angiopoetin-1 that bind to their receptors (Flt-2 and Tek/Fit-2). The soluble chimeric molecules (Flt-1/Fc and Tek/Fc) were incorporated into retroviral vectors. The vectors were infected into human breast cancer, neuroblastoma, prostate cancer cell lines. Expression of the soluble chimeric receptor molecules demonstrated a reduction of tumor weight and volume in NOD-SCID mice. Human angiogenesis was significantly decreased in the tumors expressing the chimeric molecules. We have investigated the clinical value of serum tartrate-resistant acid phosphatase (TrACP, osteoclastic marker) for the prediction of bone metastasis in patients with untreated prostate cancer in co
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mparison with PSA, ALP, and PACP Serum TrACP, PACP, ALP, and PSA levels were significantly elevated in patients with bone metastases. Logistic regression analysis demonstrated that TrACP was a significant predictor of bone metastases as well as PSA and ALP. We assessed the efficacy of a novel strategy that relies on antisense bcl-2 oligodeoxynucleotides as well as a glutathione depletor combined with diethylstilbestrol (DES) for hormone independent prostate cancer. Antisense bcl-2 oligodeoxynucleotides significantly enhanced DES induced cytotoxicity in hormone independent prostate cancer cells through the apoptotic pathway independent of augmented reactive oxygen species generation, whereas the glutathione depletor augmented cytotoxicity and reactive oxygen species generation. Statistically significant growth inhibition was achieved by a novel NFkappaB activation inhibitor, DHMEQ, in three human hormone-refractory prostate cancer cell lines, DU145, JCA-1, and PC-3, and marked levels of apoptosis were induced by DHMEQ. Furthermore, i.p. administrations of DHMEQ significantly inhibited pre-established JCA-1 s.c. tumor growth in nude. Our result indicates the possibility of a NFkappaB activation inhibitor as a new treatment strategy against hormone-refractory prostate cancer. Less
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