Inhibition of Tumor Growth by Anti-bFGF Neutralizing Antibody

Basic fibroblast growth factor (bFGF) stimulates the proliferation and differentiation of various cultured cells and induces angiogenesis in vivo. It has been reported that bFGF produced from tumor cells is involved in tumor growth as an autocrine factor which stimulates tumor cell proliferation and also as a paracrine factor which acts on neighboring vascular endothelial cells and stromal cells. We previously developed bFM-1, an immunoneutralizing monoclonal antibody to bFGF which could suppress the growth of cultured human umbilical vein endothelial cells stimulated by bFGF. bFM-1 interfered with the angiogenesis induced by bFGF on chicken chorioallantoic membrane. We tested the efficacy of in vivo suppression of growth of bFGF-producing tumor cells by in situ administration of bFM-1. bFGF producing tumor cells and non-producing myeloma cells were implanted s.c. into nude mice. bFM-1 and control monoclonal antibody were i.p. injected every 2 days at a dose of 800μg/0.2ml/head, measuring the concentrations of specific IgG in plasma by ELISA. The protein expression of bFGF and VEGF in cultured cells and implanted tumor tissues was estimated by western blot and RT-PCR. While bFM-1 in plasma was maintained in 500-700μg/ml, the weight of A431 (human squamous cell carcinoma) and HeLa cells producing solid tumors on backs of nude mice 9 days after transplantation were decreased to 42.7-63.3% of control monoclonal antibody injected tumors. The growth of tumor formed from bFGF non-producing myeloma cells, P3U1 was not inhibited by bFM-1 administration. The solid tumor growth of bFGF-producing human colorectal cancer cell line RPMI4788 cells was inhibited by 13.6-4.6% 23 days after transplantation, even though plasma bFM-1 concentration was lower. The effectiveness of bFM-1 suppression tended to be higher in tumor tissues expressing higher levels of bFGF. Partial suppressions of tumor growth by bFM-1 remind us of the involvement of another potent angiogenic factor, VEGF. However, VEGF expression level did not correlate with lower effectiveness of bFM-1. The effectiveness of suppression of tumor growth by bFM-1 administration might depend on the characteristics of tumor cells, amount of secreted bFGF and VEGF and rate of growth of solid tumor, then independent to the higher IgG concentration required to bind antigen effectively.