Antisense-MDM2 sensitizes LNCaP prostate cancer cells to androgen deprivation, radiation, and the combination in vivo.
OBJECTIVE
To test the effects of antisense (AS)-MDM2 alone and with androgen deprivation (AD), radiotherapy (RT), and AD + RT on wild-type LNCaP cells in an orthotopic in vivo model.


METHODS
Androgen-sensitive LNCaP cells were grown in the prostates of nude mice. Magnetic resonance imaging-based tumor volume and serum prostate-specific antigen (PSA) measurements were used to assess effects on tumor response. Tumor response was measured by biochemical and tumor volume failure definitions and doubling time estimates from fitted PSA and tumor volume growth curves. Expression of MDM2, p53, p21, and Ki-67 was quantified using immunohistochemical staining and image analysis of formalin-fixed tissue, analogous to methods used clinically.


RESULTS
Antisense-MDM2 significantly inhibited the growth of LNCaP tumors over the mismatch controls. The most significant increase in tumor growth delay and tumor doubling time was from AS-MDM2 + AD + RT, although the effect of AS-MDM2 + AD was substantial. Expression of MDM2 was significantly reduced by AS-MDM2 in the setting of RT.


CONCLUSIONS
This is the first in vivo investigation of the effects of AS-MDM2 in an orthotopic model and the first to demonstrate incremental sensitization when added to AD and AD + RT. The results with AD underscore the potential to affect micrometastatic disease, which is probably responsible for treatment failure in 30-40% of men with high-risk disease.
Stoyanova
Radka
R
Department of Radiation Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Hachem
Paul
P
Hensley
Harvey
H
Khor
Li-Yan
LY
Mu
Zhaomei
Z
Hammond
M Elizabeth H
ME
Agrawal
Sudhir
S
Pollack
Alan
A
D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011836:Radiation Tolerance; D011879:Radiotherapy Dosage; D014183:Transplantation, Heterologous; D047368:Tumor Burden
D016376:Oligonucleotides, Antisense; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D017430:Prostate-Specific Antigen