AbstractOsteoarthritis (OA) and degenerative disc disease (DDD) are similar diseases involving the breakdown of cartilage tissue, and a better understanding of the underlying biochemical processes involved in cartilage degeneration may allow for the development of novel biologic therapies aimed at slowing the disease process. Three members of the fibroblast growth factor (FGF) family, FGF‐2, FGF‐18, and FGF‐8, have been implicated as contributing factors in cartilage homeostasis. The role of FGF‐2 is controversial in both articular and intervertebral disc (IVD) cartilage as it has been associated with species‐ and age‐dependent anabolic or catabolic events. Recent evidence suggests that FGF‐2 selectively activates FGF receptor 1 (FGFR1) to exert catabolic effects in human articular chondrocytes and IVD tissue via upregulation of matrix‐degrading enzyme production, inhibition of extracellular matrix (ECM) accumulation and proteoglycan synthesis, and clustering of cells characteristic of arthritic states. FGF‐18, on the other hand, most likely exerts anabolic effects in human articular chondrocytes by activating the FGFR3 pathway, inducing ECM formation and chondrogenic cell differentiation, and inhibiting cell proliferation. These changes result in dispersed chondrocytes or disc cells surrounded by abundant matrix. The role of FGF‐8 has recently been identified as a catabolic mediator in rat and rabbit articular cartilage, but its precise biological impact on human adult articular cartilage or IVD tissue remains unknown. The available evidence reveals the promise of FGF‐2/FGFR1 antagonists, FGF‐18/FGFR3 agonists, and FGF‐8 antagonists (i.e., anti‐FGF‐8 antibody) as potential therapies to prevent cartilage degeneration and/or promote cartilage regeneration and repair in the future. J. Cell. Biochem. 114: 735–742, 2013. © 2012 Wiley Periodicals, Inc.

2008-05-01·The Prostate3区 · 医学

A neutralizing anti‐fibroblast growth factor (FGF) 8 monoclonal antibody shows anti‐tumor activity against FGF8b‐expressing LNCaP xenografts in androgen‐dependent and ‐independent conditions

3区 · 医学

Article

作者: Teruyoshi Imada ; Jun Ouchi ; Hideaki Kusaka ; Shiro Akinaga ; Akira Tanaka ; Kumiko Maruyama-Takahashi ; Naoki Shimada ; Yoshimi Maekawa-Tokuda ; Toshihiko Ishii ; Kenya Shitara ; Hiromasa Miyaji

AbstractBackgroundsFibroblast growth factor 8‐isoform b (FGF8b) has been detected in human clinical sex‐organ related cancers including hormone‐refractory prostate cancer. There are, however, few relevant experimental models. A murine monoclonal anti‐FGF8 antibody, KM1334, has been shown to neutralize FGF8b and inhibit the growth of androgen‐dependent mouse mammary SC‐3 cells in vitro and in vivo. In the present study, we evaluated the anti‐tumor activity of KM1334 against androgen‐dependent and ‐independent progression of FGF8b‐expressing human prostate cancer xenografts.MethodsFGF8b cDNA was transfected into androgen‐dependent human prostate cancer cell line LNCaP, and its xenograft tumors were established subcutaneously in SCID mice with or without castration. KM1334 at the dose of 400 µg/head was injected twice weekly.ResultsFGF8b‐expressing LNCaP cells secreted FGF8b, showed enhanced level of Erk1/2 phosphorylation, and showed more potent growth properties than mock‐expressing cells in vitro and in vivo. KM1334 reduced these properties in vitro, inhibited tumorigenecity in vivo (T/C = 0.33), and showed anti‐tumor activity against established tumors (T/C = 0.47) of FGF8b‐expressing cells. FGF8b‐expressing LNCaP tumors were androgen‐dependent. However, they recurred as androgen‐independent FGF8b positive tumors after castration. KM1334 also inhibited the growth of established FGF8b‐expressing tumors in the androgen‐independent states (T/C = 0.47).ConclusionsThese results indicate that humanized monoclonal antibodies, conserving the paratope of KM1334, are a promising candidate for therapy of FGF8b‐expressing clinical prostate cancers. Follow‐up studies using xenograft models with clinical FGF8b‐expressing tumors are required to validate these early findings. Prostate 68: 640–650, 2008. © 2008 Wiley‐Liss, Inc.

2005-05-15·Clinical Cancer Research1区 · 医学

A Neutralizing Anti–Fibroblast Growth Factor 8 Monoclonal Antibody Shows Potent Antitumor Activity against Androgen-Dependent Mouse Mammary Tumors In vivo

1区 · 医学

Article

作者: Tanaka, Akira ; Imada, Teruyoshi ; Maekawa-Tokuda, Yoshimi ; Shitara, Kenya ; Maruyama-Takahashi, Kumiko ; Takaba, Katsumi ; Ishii, Toshihiko ; Kusaka, Hideaki ; Sasaki, Yuka ; Akinaga, Shiro ; Shimada, Naoki

AbstractPurpose: Fibroblast growth factor 8b (FGF8b) has been implicated in oncogenesis of sex hormone–related malignancies. A murine monoclonal anti-FGF8 antibody, KM1334, has been raised against a FGF8b-derived peptide and shown to neutralize FGF8b activity in an androgen-dependent mouse mammary cell line (SC-3) in vitro growth. The purpose of this study was to evaluate KM1334 as a therapeutic agent for FGF8-dependent cancer.Experimental Design: Specificity and neutralizing activity of KM1334 were examined in vitro. In vivo therapeutic studies were done in nude mice bearing SC-3 tumors s.c.Results: KM1334 recognized FGF8b and FGF8f specifically out of four human FGF8 isoforms and showed little binding to other members of FGF family. Neutralizing activity of KM1334 was confirmed by both blocking of FGF8b binding to its three receptors (FGFR2IIIc, FGFR3IIIc, and FGFR4) and FGF8b-induced phosphorylation of FGFR substrate 2α and extracellular signal-regulated kinase 1/2 in SC-3 cells. The in vitro inhibitory effect could be extended to in vivo tumor models, where KM1334 caused rapid regression of established SC-3 tumors in nude mice. This rapid regression of tumors after KM1334 treatment was explained by two independent mechanisms: (a) decreased DNA synthesis, as evidenced by a decrease in uptake of 5-bromo-2′-deoxyuridine, and (b) induction of apoptosis as shown by the terminal deoxynucleotidyl transferase–mediated nick end labeling assay.Conclusions: KM1334 possesses strong blocking activity in vitro and antitumor activity in vivo and therefore may be an effective therapeutic candidate for the treatment of cancers that are dependent on FGF8b signaling for growth and survival.

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