Establishment of a novel mouse model for studying prostate cancer metastasis to human bone and new therapeutic strategies.

建立用于研究前列腺癌人骨转移的新型小鼠模型和新的治疗策略。

• 批准号: 13557136
• 负责人: MURAI Masaru
• 金额: $ 8万
• 依托单位: KEIO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557136/
• 关键词: prostate cancer; bone metastases; angiogenesis; bcl-2; NFkappaB; VEGF; ヒト腫瘍血管新生; 遺伝子治療; NOD; SCIDマウス; ヒト腫瘍血管新; レトロウイルスベクター; 血管内皮細胞

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 … More 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

源自前列腺的肿瘤具有转移至骨的特殊倾向。我们使用 HuBone-NOD-SCID 小鼠进行了一系列旨在抑制人类血管生成的实验，以开发骨转移的治疗策略。肿瘤细胞产生与其受体（Flt-2 和 Tek/Fit-2）结合的血管生成因子，例如 VECF 和血管生成素-1。将可溶性嵌合分子（Flt-1/Fc 和 Tek/Fc）整合到逆转录病毒载体中。这些载体被感染到人类乳腺癌、神经母细胞瘤、前列腺癌细胞系中。可溶性嵌合受体分子的表达证明了 NOD-SCID 小鼠肿瘤重量和体积的减少。在表达嵌合分子的肿瘤中，人类血管生成显着减少。我们研究了血清抗酒石酸酸性磷酸酶（TrACP，破骨细胞标志物）与 PSA、ALP 和 PACP 相比，对未经治疗的前列腺癌患者预测骨转移的临床价值。骨转移患者的血清 TrACP、PACP、ALP 和 PSA 水平显着升高。 Logistic 回归分析表明，TrACP 以及 PSA 和 ALP 是骨转移的重要预测因子。我们评估了一种新策略的功效，该策略依赖于反义 bcl-2 寡脱氧核苷酸以及谷胱甘肽消耗剂与己烯雌酚 (DES) 联合治疗激素非依赖性前列腺癌。反义 bcl-2 寡脱氧核苷酸通过不依赖活性氧生成的细胞凋亡途径显着增强 DES 在激素非依赖性前列腺癌细胞中诱导的细胞毒性，而谷胱甘肽消耗剂则增强细胞毒性和活性氧生成。新型 NFkappaB 激活抑制剂 DHMEQ 在三种人类激素难治性前列腺癌细胞系 DU145、JCA-1 和 PC-3 中实现了统计学上显着的生长抑制，并且 DHMEQ 诱导了显着水平的细胞凋亡。此外，ip。 DHMEQ 的施用显着抑制了预先建立的 JCA-1 s.c.。肿瘤在裸体中生长。我们的结果表明 NFkappaB 激活抑制剂有可能作为激素难治性前列腺癌的新治疗策略。较少的

项目成果

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OHIGASHI T, UENO M, NONAKA S, DEGUCHI N, MURAI M.: "Bcl-2 and androgen receptor gene expression in androgen-independent subclone derived from mouse androgen-dependent cells."Cancer Invest.. 20. 730-736 (2002)

OHIGASHI T、UENO M、NONAKA S、DEGUCHI N、MURAI M.：“源自小鼠雄激素依赖性细胞的雄激素非依赖性亚克隆中的 Bcl-2 和雄激素受体基因表达。”Cancer Invest.. 20. 730-736 (2002

Nguyen, H., Hozumi, N.et al.: "Isolation of human single chain antibodies (scFv) against human TNF-α from human peripheral blood lymphocyte-SCID mice"Human Antibodies. 11. 65-72 (2002)

Nguyen, H., Hozumi, N.等人：“从人外周血淋巴细胞-SCID 小鼠中分离抗人 TNF-α 的人单链抗体 (scFv)”Human Antibodies。

KOHYAMA M, SUGAHARA D, HOSOKAWA H, KUBO M, HOZUMI N.: "IL-4 mediated development of TGF-b1 producing cells from naive CD4+ T cells through a STAT6 indenendent mechanism."Eur J Immunol. 31. 3659-3666 (2001)

KOHYAMA M、SUGAHARA D、HOSOKAWA H、KUBO M、HOZUMI N.：“IL-4 通过 STAT6 独立机制介导从初始 CD4 T 细胞产生 TGF-b1 的细胞的发育。”Eur J Nutrition。

HORIGUCHI Y., NUKAYA I., OKAZAWA K., KAWASHIMA I., FIKES J., SETTE A., TACHIBANA M., TAKESAKO K., MURAI M.: "Screening of HLA-A24-restricted epitope peptides from prostate-specific membrane antigen that induced specific antitumor cytotoxic lymphocytes."Cl

HORIGUCHI Y.、NUKAYA I.、OKAZAWA K.、KAWASHIMA I.、FIKES J.、SETTE A.、TACHIBANA M.、TAKESAKO K.、MURAI M.：“从前列腺特异性中筛选 HLA-A24 限制性表位肽