Growth inhibition of prostate cancer xenografts by halofuginone.
BACKGROUND
Halofuginone, an inhibitor of collagen type I synthesis, is an anti-angiogenic agent. Here we evaluated the efficacy of halofuginone to inhibit prostate cancer (PC) xenografts representing various phenotypes of the disease.


METHODS
An androgen-dependent (CWR22), an androgen-independent (PC3), and a neuroendocrine (WISH-PC2) PC xenograft were used. Halofuginone was given orally or injected intraperitoneally. Tumor size, collagen alpha1(I) gene expression (in situ hybridization), collagen content (sirius red staining), angiogenesis (immunohistochemistry with factor VIII antibodies), and apoptosis/necrosis (DNA fragmentation) were evaluated.


RESULTS
Halofuginone inhibited the growth of all subcutaneously implanted xenografts and of WISH-PC2 when transplanted orthotopically. The effect was dose-dependent (WISH-PC2) and accompanied by decrease in plasma PSA levels (CWR22). In all xenografts, halofuginone inhibited collagen alpha1(I) gene expression, reduced collagen content, and endothelial cell number resulting in an increase in apoptosis/necrosis.


CONCLUSIONS
Oral administration of halofuginone slowed the progression of PC xenografts representing a broad range of phenotypes. Halofuginone may become a new modality for PC prevention.
Gavish
Zohar
Z
Institute of Animal Science, The Volcani Center, PO Box 6, Bet Dagan, Israel.
Pinthus
Jehonathan H
JH
Barak
Vivian
V
Ramon
Jacob
J
Nagler
Arnon
A
Eshhar
Zelig
Z
Pines
Mark
M
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000284:Administration, Oral; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D024042:Collagen Type I / Q000096:biosynthesis; D004273:DNA, Neoplasm; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009336:Necrosis; D009389:Neovascularization, Pathologic; D010641:Phenotype; D010880:Piperidines; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones
D000728:Androgens; D000970:Antineoplastic Agents; D024042:Collagen Type I; D004273:DNA, Neoplasm; D010880:Piperidines; D011799:Quinazolines; D052999:Quinazolinones; C010176:halofuginone