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

Abstract

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-sensitiveLNCaP 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.

Expression of Bcl-2, p53, and MDM2 in Localized Prostate Cancer With Respect to the Outcome of Radical Radiotherapy Dose Escalation

“…The current study was larger, had many more events for analysis, and did not show any significant association between MDM2 expression and treatment outcome. Notwithstanding that antisense strategies to target MDM2 have been reported to act as a radiosensitizer in a mouse model of prostate cancer (41), the clinical data currently available suggest that Bcl-2 may be a more relevant target for this approach (42).…”

MDM2 and Ki-67 Predict for Distant Metastasis and Mortality in Men Treated With Radiotherapy and Androgen Deprivation for Prostate Cancer: RTOG 92-02

“…21,22 In our laboratory, MDM2 knockdown by antisense oligonucleotide-sensitized, androgensensitive, and selected androgen-insensitive, prostate cancer cells to androgen deprivation and RT. [6][7][8][9] Because MDM2 is overexpressed in some prostate cancers and because overexpression affects response to RT and androgen deprivation, this biomarker has the potential for identification of patients who would benefit from more aggressive therapy, including agents that knock down or interfere with MDM2 actions.…”

“…[1][2][3] In addition, MDM2 interacts with other regulatory proteins, such as pRB 4 and E2F-1, 5 independent of p53. In prostate cancer, MDM2 knockdown increases the sensitivity of the tumor cells to androgen deprivation and radiation both in vitro and in vivo [6][7][8] and enhances tumor growth inhibition in androgen-insensitive cells. 9 In an earlier report that evaluated the association between MDM2 overexpression and outcome of patients with prostate cancer, we observed a relationship to Gleason score and a trend of an association with distant metastases (DM) in men treated with radiation therapy (RT) with or without shortterm androgen deprivation (STAD) in Radiation Therapy Oncology Group (RTOG) protocol 86-10.…”

Synergistic Suppression of Prostatic Cancer Cells by Coexpression of BothMurine Double Minute 2Small Interfering RNA and Wild-Typep53Gene In Vitro and In Vivo

“…Tumors with overexpression of MDM2 were resistant to p53 gene therapy (Wiman, 2006). Reportedly, prostate tumors with MDM2 knockdown were sensitive to radiation therapy both in vitro and in vivo (Mu et al, 2004a(Mu et al, ,b, 2008Stoyanova et al, 2007). Therefore, an antitumor strategy interfering with the p53-MDM2 feedback loop holds promise to reinstate the p53 tumor-suppressing pathway (Wade and Wahl, 2009).…”