Imaging androgen receptor function during flutamide treatment in the LAPC9 xenograft model.
The current understanding of the response of androgen receptor to pharmacologic inhibitors in prostate cancer is derived primarily from serum prostate-specific antigen (PSA) levels. In this study, we test whether a novel androgen receptor-specific molecular imaging system is able to detect the action of the antiandrogen flutamide on androgen receptor function in xenograft models of prostate cancer. Adenoviruses bearing an optical imaging cassette containing an androgen receptor-responsive two-step transcriptional amplification system were injected into androgen-dependent and hormone-refractory tumors of animals undergoing systemic time-controlled release of the antiandrogen flutamide. Imaging of tumors with a cooled charge-coupled device camera revealed that the response of AdTSTA to flutamide is more sensitive and robust than serum PSA measurements. Flutamide inhibits the androgen signaling pathway in androgen-dependent but not refractory tumors. Analysis of androgen receptor and RNA polymerase II binding to the endogenous PSA gene by chromatin immunoprecipitation revealed that flutamide treatment and androgen withdrawal have different molecular mechanisms. The application of imaging technology to study animal models of cancer provides mechanistic insight into antiandrogen targeting of androgen receptor during disease progression.
Ilagan
Romyla
R
Department of Biological Chemistry, School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, CHS 33-142, Los Angeles, California 90095-1737, USA. milagan@ucla.edu
Zhang
Liquin Joann
LJ
Pottratz
Jill
J
Le
Kim
K
Salas
Sussan
S
Iyer
Meera
M
Wu
Lily
L
Gambhir
Sanjiv S
SS
Carey
Michael
M
D000256:Adenoviridae / Q000235:genetics; D000728:Androgens / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D018450:Disease Progression; D005485:Flutamide / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000096:biosynthesis* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012319:RNA Polymerase II / Q000378:metabolism; D011944:Receptors, Androgen / Q000502:physiology*; D013997:Time Factors; D014158:Transcription, Genetic
C410798:AR protein, human; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D011944:Receptors, Androgen; D005485:Flutamide; D012319:RNA Polymerase II; D017430:Prostate-Specific Antigen