Adenovirus E2F1 Overexpression Sensitizes LNCaP and PC3 Prostate Tumor Cells to Radiation In Vivo

Journal Article · Mon Jan 31 23:00:00 EST 2011 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2010.08.013· OSTI ID:21491595

Udayakumar, Thirupandiyur S; Stoyanova, Radka; Hachem, Paul; Ahmed, Mansoor M ^[1]; Pollack, Alan ^[1]

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1. Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (United States)

Purpose: We previously showed that E2F1 overexpression radiosensitizes prostate cancer cells in vitro. Here, we demonstrate the radiosensitization efficacy of adenovirus (Ad)-E2F1 infection in growing (orthotopic) LNCaP and (subcutaneous) PC3 nude mice xenograft tumors. Methods and Materials: Ad-E2F1 was injected intratumorally in LNCaP (3 x 10{sup 8} plaque-forming units [PFU]) and PC3 (5 x 10{sup 8} PFU) tumors treated with or without radiation. LNCaP tumor volumes (TV) were measured by magnetic resonance imaging, caliper were used to measure PC3 tumors, and serum prostate-specific antigen (PSA) levels were determined by enzyme-linked immunosorbent assay. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, and key proteins involved in cell death signaling were analyzed by Western blotting. Results: Intracellular overexpression of Ad-E2F1 had a significant effect on the regression of TV and reduction of PSA levels relative to that of adenoviral luciferase (Ad-Luc)-infected control. The in vivo regressing effect of Ad-E2F1 on LNCaP tumor growth was significant (PSA, 34 ng/ml; TV, 142 mm{sup 3}) compared to that of Ad-Luc control (PSA, 59 ng/ml; TV, 218 mm{sup 3}; p <0.05). This effect was significantly enhanced by radiation therapy (compare: Ad-E2F1+RT/PSA, 16 ng/ml, and TV, 55 mm{sup 3} to Ad-Luc+RT/PSA, 42 ng/ml, and TV, 174 mm{sup 3}, respectively; p <0.05). For PC3 tumors, the greatest effect was observed with Ad-E2F1 infection alone; there was little or no effect when radiotherapy (RT) was combined. However, addition of RT enhanced the level of in situ apoptosis in PC3 tumors. Molecularly, addition of Ad-E2F1 in a combination treatment abrogated radiation-induced BCL-2 protein expression and was associated with an increase in activated BAX, and together they caused a potent radiosensitizing effect, irrespective of p53 and androgen receptor functional status. Conclusions: We show here for the first time that ectopic overexpression of E2F1 in vivo, using an adenoviral vector, significantly inhibits orthotopic p53 wild-type LNCaP tumors and subcutaneous p53-null PC3 tumors in nude mice. Furthermore, we demonstrate that E2F1 strongly sensitizes LNCaP tumors to RT. These findings suggest that E2F1 overexpression can sensitize prostate tumor cells in vivo, independent of p53 or androgen receptor status.

• OSTI ID: 21491595
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 2 Vol. 79; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
ADENOVIRUS
ANIMAL CELLS
ANIMALS
ANTIGENS
APOPTOSIS
BIOLOGICAL PATHWAYS
BODY
DIAGNOSTIC TECHNIQUES
DISEASES
GLANDS
IN VIVO
MALE GENITALS
MAMMALS
MEDICINE
MICE
MICROORGANISMS
NEOPLASMS
NMR IMAGING
NUCLEAR MEDICINE
ONCOGENIC VIRUSES
ORGANS
PARASITES
PROSTATE
RADIOLOGY
RADIOSENSITIVITY EFFECTS
RADIOTHERAPY
RODENTS
THERAPY
TUMOR CELLS
VERTEBRATES
VIRUSES