Adenovirus E2F1 overexpression sensitizes LNCaP and PC3 prostate tumor cells to radiation in vivo.

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 × 10(8) plaque-forming units [PFU]) and PC3 (5 × 10(8) PFU) tumors treated with or without radiation.

MR-guided focused ultrasound: enhancement of intratumoral uptake of [³H]-docetaxel in vivo.

The purpose of this study is to quantify the enhancement of [³H]-docetaxel in implanted prostate tumors treated with MR-guided pulsed focused ultrasound (MRgFUS). Human prostate cancer, LNCaP cells in 25 µl, were implanted into the prostates of male nude mice. The tumor growth was directly monitored on MRI.

PKA knockdown enhances cell killing in response to radiation and androgen deprivation.

The therapeutic efficacy of Gem®231, a second generation antisense molecule targeted to the RIα subunit of PKA(RIα) (AS-PKA), administered in combination with androgen deprivation (AD) and radiation therapy (RT), was examined in androgen sensitive (LNCaP) and insensitive (PC3) cell lines. Apoptosis was assayed by Caspase 3 + 7 activity and Annexin V binding. AS-PKA significantly increased apoptosis in vitro from RT (both lines), with further increases in LNCaP cells grown in AD medium.

Antisense MDM2 enhances E2F1-induced apoptosis and the combination sensitizes androgen-sensitive [corrected] and androgen-insensitive [corrected] prostate cancer cells to radiation.

We have previously shown in separate studies that MDM2 knockdown via antisense MDM2 (AS-MDM2) and E2F1 overexpression via adenoviral-mediated E2F1 (Ad-E2F1) sensitized prostate cancer cells to radiation. Because E2F1 and MDM2 affect apoptosis through both common and independent pathways, we hypothesized that coupling these two treatments would result in increased killing of prostate cancer cells. In this study, the effect of Ad-E2F1 and AS-MDM2 in combination with radiation was investigated in three prostate cancer cell lines: LNCaP cells, LNCaP-Res cells [androgen insensitive with functional p53 and androgen receptor (AR)], and PC3 cells (androgen insensitive, p53(null), and AR(null)).

Antisense MDM2 enhances the response of androgen insensitive human prostate cancer cells to androgen deprivation in vitro and in vivo.

Background: Antisense MDM2 oligonucleotide (AS-MDM2) sensitizes androgen sensitive LNCaP cells to androgen deprivation (AD) in vitro and in vivo. In this study, we investigated the effects of AS-MDM2 combined with AD on androgen resistant LNCaP (LNCaP-Res) and moderately androgen resistant bcl-2 overexpressing LNCaP (LNCaP-BST) cells.

Methods: The LNCaP-Res cell line was generated by culturing LNCaP cells in medium containing charcoal-stripped serum for more than 1 year.

Antisense-MDM2 sensitizes LNCaP prostate cancer cells to androgen deprivation, radiation, and the combination in vivo.

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.

Antisense Bcl-2 sensitizes prostate cancer cells to radiation.

Background: Bcl-2 is anti-apoptotic and overexpression is associated with prostate tumor aggressiveness. We hypothesized that Bcl-2 has a role in prostate cancer radiation (RT) response. The relationship of Bcl-2 expression in four prostate cancer cell lines, and the effect of modulating expression with a Bcl-2 antisense oligonucleotide (G3139, Genasense, oblimersen sodium, Genta Incorporated), to RT was examined.

Adenoviral-E2F-1 radiosensitizes p53wild-type and p53null human prostate cancer cells.

Purpose: E2F-1 is a transcription factor that enhances the radiosensitivity of various cell lines by inducing apoptosis. However, there are conflicting data concerning whether this enhancement is mediated via p53 dependent pathways. Additionally, the role of E2F-1 in the response of human prostate cancer to radiation has not been well characterized.

Antisense MDM2 oligonucleotides restore the apoptotic response of prostate cancer cells to androgen deprivation.

Background: Early in the malignant transformation of prostate epithelial cells, the apoptotic response to androgen deprivation (AD) is lost and the principle response is a slowing of cell growth. In this study, we tested whether interruption of MDM2 function using antisense MDM2 oligonucleotide (AS) affects the apoptotic response of prostate cancer cells to AD.

Methods: Wild type LNCaP cells and MDM2-overexpressing (LNCaP-MST) cells were treated with AS alone or in combination with AD.

Antisense MDM2 sensitizes prostate cancer cells to androgen deprivation, radiation, and the combination.

Purpose: Antisense MDM2 (AS) sensitizes a variety of tumor cell types, including prostate cancer, to radiation and chemotherapy. We have previously described that AS enhances the apoptotic response to androgen deprivation (AD) and that this translates into a reduction in overall cell survival, as measured by clonogenic assay. Because AD + radiation (RT) is a key strategy for the treatment of men with high-risk prostate cancer, AS was tested for the ability to sensitize cells to the combination of AD+RT.

Effect of sequencing of androgen deprivation and radiotherapy on prostate cancer growth.

Purpose: Androgen deprivation (AD) is frequently combined with radiotherapy (RT); however, the optimal sequence in vivo is currently unknown. Previous published work from our laboratory demonstrated that AD with RT was consistent with at least an additive, and possibly supra-additive, effect with the combined approach. We, therefore, performed additional experiments to elucidate the optimal sequence.