Antisense c-mycRetroviral Vector Suppresses Established Human Prostate Cancer

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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. Advanced prostate cancer over-expresses c-myc. A novel strategy to combat advanced prostate cancer utilized a replication-incompetent retrovirus which contained a mouse mammary tumor virus (MMTV) promoter to express antisense c-myc in prostate cells. Direct injection of MMTV-antisense c-myc virus into established DU145 tumors in nude mice produced a 94.5% reduction in tumor size compared to controls by 70 days. MMTV-antisense c-myc-transduced DU145 tumors had increased differentiation, stromal response, and apoptosis and decreased invasion. MMTV-antisense c-myc retrovirus appears to mediate its antitumor effects by suppressing c-myc, which is associated with a decreased bcl-2 protein.