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Antisense c-myc retroviral vector suppresses established human prostate cancer
M S Steiner1, C T Anthony, Y Lu
1Department of Urology, Vanderbilt University School of Medicine, Nashville, TN 37235, USA.
Abstract:
Prostate cancer eventually becomes androgen resistant, resumes growth, and kills the patient. Characterization of genetic events that lead to androgen refractory prostatic neoplasia has revealed the frequent overexpression of c-myc and uncontrolled prostate cancer proliferation. A novel strategy to combat advanced prostate cancer utilized a replication incompetent retrovirus that contained the mouse mammary tumor virus (MMTV) promoter within the retroviral vector to allow transcription of antisense c-myc gene within target prostate tumor cells. The transduction of cultured DU145 cells by XM6:MMTV-antisense c-myc RNA retrovirus did not affect cell proliferation in culture, yet a single direct injection of MMTV-antisense c-myc viral media into established DU145 tumors in nude mice produced a 94.5% reduction in tumor size compared to tumors treated with control virus MTMV sense fos and untreated tumor by 70 days. Two animals in the antisense c-myc-treated group had complete regression of their tumors. Histopathological examination of the tumors revealed that MMTV-antisense c-myc-transduced DU145 tumors had increased tumor cell differentiation, decreased invasion, and a marked stromal response. The mechanism for the antitumor effect of MMTV-antisense c-myc retrovirus appears to be suppression of c-myc mRNA and protein, and decreased bcl-2 protein. The in vivo transduction of prostate cancer cells with MMTV-antisense c-myc retroviruses reduced tumor growth by suppressing c-myc, resulting in the down-regulation of bcl-2 protein. Consequently, the MMTV-antisense c-myc retrovirus may be useful for gene therapy against advanced, hormone-refractory prostate cancer.
Insights
Gene therapy using MMTV-antisense c-myc retrovirus effectively reduced advanced prostate cancer growth in mice. This approach suppressed c-myc, leading to tumor regression and increased cell differentiation.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Prostate cancer often becomes androgen-resistant, leading to uncontrolled proliferation.
- Overexpression of c-myc is frequently observed in advanced prostate cancer.
- Current treatments for hormone-refractory prostate cancer have limited efficacy.
Purpose of the Study:
- To investigate the potential of antisense c-myc gene therapy for advanced prostate cancer.
- To evaluate the efficacy of a novel retroviral vector (XM6:MMTV-antisense c-myc RNA) in reducing tumor growth.
- To elucidate the molecular mechanisms underlying the antitumor effects.
Main Methods:
- Development of a replication-incompetent retrovirus containing the MMTV promoter for antisense c-myc transcription.
- Transduction of DU145 prostate cancer cells in vitro and in vivo.
- Direct injection of viral media into established DU145 tumors in nude mice.
- Assessment of tumor size, histopathology, and molecular markers (c-myc, bcl-2).
Main Results:
- Direct injection of MMTV-antisense c-myc viral media significantly reduced DU145 tumor size by 94.5% in mice.
- Complete tumor regression was observed in two animals treated with the antisense c-myc retrovirus.
- Histopathological analysis showed increased tumor cell differentiation, decreased invasion, and a marked stromal response in treated tumors.
- Antisense c-myc treatment suppressed c-myc mRNA and protein, and decreased bcl-2 protein levels.
Conclusions:
- MMTV-antisense c-myc retrovirus demonstrates significant antitumor activity against established prostate cancer xenografts.
- The mechanism involves suppression of c-myc, leading to down-regulation of bcl-2 and promoting tumor cell differentiation.
- This retroviral gene therapy strategy holds promise for treating advanced, hormone-refractory prostate cancer.