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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
Author(s) -
MaruyamaTakahashi Kumiko,
Shimada Naoki,
Imada Teruyoshi,
MaekawaTokuda Yoshimi,
Ishii Toshihiko,
Ouchi Jun,
Kusaka Hideaki,
Miyaji Hiromasa,
Akinaga Shiro,
Tanaka Akira,
Shitara Kenya
Publication year - 2008
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20728
Subject(s) - lncap , prostate cancer , androgen , cancer research , dihydrotestosterone , in vivo , medicine , androgen receptor , endocrinology , monoclonal antibody , biology , antibody , cancer , hormone , immunology , microbiology and biotechnology
Backgrounds Fibroblast 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. Methods FGF8b 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. Results FGF8b‐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). Conclusions These 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.