Anti-tumor effect of novel tumor necrosis factor (TNF-S) to human urological cancer in vitro and in vivo

• Project/Area Number: 63570755
• Research Category: Grant-in-Aid for General Scientific Research (C)
• Allocation Type: Single-year Grants
• Research Field: Urology
• Research Institution: Saitama Medical School
• Principal Investigator: KATO Mikio Saitama Medical School, Department of Urology, Associate Professor, 医学部, 助教授 (80096213)
• Co-Investigator(Kenkyū-buntansha): SOMA Genichiro Teikyo University, Biotechnolgy Research Center, Associate Professor, 生物工学研究センター, 助教授 (00158990)
• Project Period (FY): 1988 – 1989
• Project Status: Completed (Fiscal Year 1989)
• Budget Amount: ¥1,900,000 (Direct Cost: ¥1,900,000); Fiscal Year 1989: ¥600,000 (Direct Cost: ¥600,000); Fiscal Year 1988: ¥1,300,000 (Direct Cost: ¥1,300,000)
• Keywords: Novel TNF / Human urological cancer / Antitumor effect / 腫瘍壊死因子 / 人尿路系悪性腫瘍 / ヌードマウス移植系 / 増殖抑制

Research Abstract

Novel tumor necrosis factor (TNF-S) with higher basicity than conventional human TNF- alpha in the N-terminal region had showed a broader cytotoxicity to tumor cells and less toxicity than TNF-alpha. We investigated antitumor effects of TNF-S to human urological cancer cells in vitro and in vivo. We used four bladder cancer cell lines (T-24, HUB-4, HUB-6 and HUB-15) and a prostate cancer cell line, PC-3, in vitro. Although little cytostatic effect was seen when these cells were cultured with high dose TNF- alpha, ten to a hundred times higher cytostatic effects were seen on the cell lines with TNF-S produced by THP-1 cells and recombinant TNF-Scwl that was one type of rTNF-Ss. Because of the quite poor yield of rTNF-Scwl, further analyses of cytotoxicity against T-24 were carried out on rTNF-Scw2 and rTNF-Sam2. The cytotoxic effect of rTNF-Scw2 to T-24 was higher than TNF-alpha, but less than rTNF-Scwl. No cytotoxic effect of rTNF-Scw2 to T-24 was found at less than 1,000 u/ml without anticancer agents after 18 hours. A slight increase of the cytotoxicity at 1,000 u/ml for rTTiF-Scw2 was found by the respective addition of four anticancer agents that were Act-D, ADM, MMG and CDDP. It seemed that the cytotoxic effect of TNF-S against urological cancer cells was not sufficient in vitro. On the contrary to the in vitro result, there was significant slowing of growth in a bladder cancer xenograft by a singular use of TNF-S. A combination effect of TNF-S and CDDP in the same xenograft was higher than the effect of singular administration of cDDP. Total tumor regression was observed in three of eight xenografts by the combination therapy. When a chimeric protein, Thymosin beta4/TNF-S, was given intrtumorally with Lentinan, prostate cancer xenografts were partially regressed. According to the in vivo results, we suspect that TNF-S has a certain therapeutic efficacy against human urological tumors and the efficacy may be enhanced by the additional anticancer agents or other biological response modifiers.