Study on the induction of cytotoxic lymphocytes that act on urological tumors and its clinical application

泌尿系肿瘤细胞毒性淋巴细胞的诱导及其临床应用研究

• 批准号: 03454385
• 负责人: YOSHIDA Osamu
• 金额: $ 3.97万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-03454385/
• 关键词: Urological tumor; Cytotoxic Lymphocyte; BCG; CK-432; CDDP; PSK; TNF; BSO; 膀胱腫瘍; 腎癌; 末梢血リンパ球; NK細胞; Tリンパ球; LAK細胞; 免疫療法; Krestin(PSK); Hyperthermia; 臨床応用

We demonstrate the following results :1. Protein-bound polysaccharide Kreha ( PSK ) augments cytotoxic activity of peripheral blood lymphocytes ( PBL ) against urinary bladder tumor cells in vitro and in vivo in patients with urinary bladder tumor. The PSK-mediated enhancement of cytotoxicity of PBL may be largely due to an alpha-1, 4-glucan of less than 50 kd.2. Bacillus Calmette-Guerin ( BCG ) activates the tumor killing system through stimulation of effector cells and elevation of target cell susceptibility to lysis by cytotoxic lymphocytes in patients with urinary bladder tumor. Furthermore, BCG-augmented cytotoxicity may be specifically oriented to urinary bladder tumor cells.3. Combination treatment of MBT-2 murine urinary bladder tumor cell line transplanted into C3H/He mice with BCG and exogenous fibrinogen prolongs accumulation of BCG by trapping BCG in fibrin meshwork, and induces marked infiltration of inflammatory cells into tumor stroma, causing marked regression of the tu … More mor.4. Like BCG, OK-432 activates the autologous tumor killing system through stimulation of effector cells and enhancement of target cell susceptibility to lysis by effector cells in patients with urinary bladder tumor. Moreover, the OK-432-augmented target sensitivity to lysis by cytotoxic lymphocytes may be oriented specifically to urinary bladder tumor cells.5. Cis-diamminedichloroplatinum ( II ) ( CDDP ) has an augmenting effect on the susceptibility of urinary bladder tumor cells to the cell-mediated cytotoxicity partly through a modification of cell membrane and inhibition of DNA synthesis.6. Cytotoxic lymphocytes activated by tumor cells produce various kinds of cytokines such as tumor necrosis factor-alpha ( TNF-alpha ) which exert cytotoxic activity against tumor cells. TNF-alpha in combination with CDDP, buthionine sulfoximine ( BSO ) or pentoxifylline ( PTX ) overcomes the TNF-alpha-resistance of renal cell carcinoma cells. Downregulation of TNF-alpha mRNA by CDDP, BSO or PTX may play a role in the enhanced cytotoxicity seen with TNF-alpha in combination with CDDP, BSO or PTX. Less

1.蛋白结合多糖Kreha(PSK)可增强膀胱肿瘤患者外周血淋巴细胞(PBL)在体内外对膀胱肿瘤细胞的杀伤活性。PSK介导的PBL细胞毒性的增强可能主要是由于小于50kd2的α-1，4-葡聚糖所致。卡介苗(BCG)在膀胱肿瘤患者中通过刺激效应细胞和提高细胞毒性淋巴细胞对靶细胞裂解的敏感性来激活肿瘤杀伤系统。此外，卡介苗增强的细胞毒作用可能是针对膀胱肿瘤细胞的。卡介苗与外源性纤维蛋白原联合应用可延长卡介苗在纤维蛋白网络中的蓄积时间，并诱导炎性细胞向肿瘤间质侵袭，使TU…明显消退。更多的时间。与卡介苗一样，OK-432通过刺激效应细胞和增强效应细胞对膀胱肿瘤患者的靶细胞裂解的敏感性来激活自体肿瘤杀伤系统。此外，OK-432增强的细胞毒性淋巴细胞裂解的靶向敏感性可能是针对膀胱肿瘤细胞的。顺式二氨基氯铂(CDDP)通过修饰细胞膜，抑制DNA合成，增强膀胱肿瘤细胞对细胞毒作用的敏感性。肿瘤细胞激活的细胞毒性淋巴细胞产生多种细胞因子，如肿瘤坏死因子-α，对肿瘤细胞具有细胞毒活性。肿瘤坏死因子-α联合顺铂、丁硫氨酸亚磺胺(BSO)或己酮可可碱(PTX)可克服肾癌细胞对肿瘤坏死因子-α的耐药性。CDDP、BSO或PTX对肿瘤坏死因子-α基因表达的下调可能在联合应用肿瘤坏死因子-α增强细胞毒作用中起一定作用。较少

项目成果

Akihiro Krishita: "Post-radiation treatment with OK-432 can prevent radiation induced bone marrow death." International Journal of Radiation Biology. 59. 711-716 (1991)

Akihiro Krishita：“用 OK-432 进行放射治疗可以预防放射引起的骨髓死亡。”

Youichi Mizutani: "Overcoming CDDP resistance of human ovarian tumor cells by combination treatment with CDDP and TNF-α." CANCER. 72. 809-818 (1993)

Youichi Mizutani：“通过 CDDP 和 TNF-α 联合治疗克服人类卵巢肿瘤细胞的 CDDP 耐药性。”72. 809-818 (1993)。

吉田 修: "臨床医学の展望-診断及び治療上の進歩:泌尿器科:臨床免疫学" 医事新報. 3644. 46-47 (1994)

Osamu Yoshida：“临床医学的观点 - 诊断和治疗的进展：泌尿学：临床免疫学”Ijishinpo 3644. 46-47 (1994)。

水谷 陽一: "BCG,フィブリノーゲン混合投与によるBCG局所療法の抗腫瘍効果の増強" BIOTHERAPY. (発表予定). (1994)

Yoichi Mizutani：“通过混合使用 BCG 和纤维蛋白原增强局部 BCG 治疗的抗肿瘤作用”（即将发表）。

Mizutani, Y.and Bonavida, B.: "Enhanced sensitivity of a human ovarian cancer cell line ( OVC-8 ) to TNF-alpha by pentoxifylline." Biotherapy. (in press). (1994)

Mizutani, Y. 和 Bonavida, B.：“己酮可可碱增强人卵巢癌细胞系 (OVC-8) 对 TNF-α 的敏感性。”