Antisense-MDM2 Sensitizes LNCaP Prostate Cancer Cells to Androgen Deprivation, Radiation, and the Combination In Vivo

Journal Article · Sun Jul 15 04:00:00 EDT 2007 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2007.03.047· OSTI ID:20953568

Stoyanova, Radka ^[1]; Hachem, Paul ^[1]; Hensley, Harvey ^[2]; Khor, L -Y ^[1]; Zhaomei, Mu ^[1]; Hammond, M Elizabeth H. ^[3]; Agrawal, Sudhir ^[4]; Pollack, Alan ^[1]

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1. Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA (United States)
2. Department of Basic Science, Fox Chase Cancer Center, Philadelphia, PA (United States)
3. Department of Pathology, LDS Hospital, Intermountain Health Care, Salt Lake City, UT (United States)
4. Idera Pharmaceuticals, Cambridge, MA (United States)

Purpose: 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.

• OSTI ID: 20953568
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 4 Vol. 68; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
ANDROGENS
ANTIGENS
CARCINOMAS
FAILURES
FORMALDEHYDE
IMAGE PROCESSING
IN VIVO
MICE
NMR IMAGING
PROSTATE
RADIOTHERAPY