Effective prostate cancer chemopreventive intervention with green tea polyphenols in the TRAMP model depends on the stage of the disease.
OBJECTIVE
We have shown previously that oral feeding of green tea polyphenols (GTP) to transgenic adenocarcinoma of the mouse prostate mice in a purely chemopreventive setting significantly inhibits prostate cancer development. To translate this to a human situation, the present study was designed to identify the stage of prostate cancer that is most vulnerable to chemopreventive intervention by GTP.


METHODS
GTP infusion (0.1% in drinking water) to transgenic adenocarcinoma of the mouse prostate was initiated at ages representing different stage of the disease: (a) 6 weeks (group 1, normal prostate), (b) 12 weeks (group 2, prostatic intraepithelial neoplasia), (c) 18 weeks (group 3, well-differentiated adenocarcinoma), and (b) 28 weeks (group 4, moderately differentiated adenocarcinoma). At age 32 weeks, subsets of animals were evaluated by magnetic resonance imaging, ultrasound, and prostate weight and for serum insulin-like growth factor (IGF)-I/IGF binding protein-3 and IGF signaling.


RESULTS
Tumor-free survival was extended to 38 weeks (P < 0.001) in group 1, 31 weeks (P < 0.01) in group 2, and 24 weeks (P < 0.05) in group 3 compared with 19 weeks in water-fed controls. Median life expectancy was 68 weeks in group 1, 63 weeks in group 2, 56 weeks in group 3, and 51 weeks in group 4 compared with 42 weeks in the control mice. IGF-I and its downstream targets including phosphatidylinositol 3-kinase, pAkt, and phosphorylated extracellular signal-regulated kinase were significantly inhibited only when intervention was initiated early when prostatic intraepithelial neoplasia lesions were common.


CONCLUSIONS
Our studies indicate that chemopreventive potential of GTP decreases with advancing stage of the disease and underscore the need to design appropriate chemoprevention clinical trails.
Adhami
Vaqar Mustafa
VM
Department of Dermatology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Siddiqui
Imtiaz Ahmad
IA
Sarfaraz
Sami
S
Khwaja
Sabih Islam
SI
Hafeez
Bilal Bin
BB
Ahmad
Nihal
N
Mukhtar
Hasan
H
D000230:Adenocarcinoma / Q000737:chemistry / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D005419:Flavonoids / Q000627:therapeutic use*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009367:Neoplasm Staging; D010636:Phenols / Q000627:therapeutic use*; D059808:Polyphenols; D019048:Prostatic Intraepithelial Neoplasia / Q000517:prevention & control; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D013662:Tea
D016588:Anticarcinogenic Agents; D005419:Flavonoids; D018972:Insulin-Like Growth Factor Binding Protein 3; D010636:Phenols; D059808:Polyphenols; D013662:Tea; D007334:Insulin-Like Growth Factor I