Apoptosis in Prostate Cancer
Abstract
To develop new therapeutic means to treat androgen-independent prostate cancer, we hypothesized that the apoptotic pathway of prostate cancer cells can be manipulated for therapeutic purposes. In support of our hypothesis, we presented preliminary data showing that a molecule of the apopotic pathway, caspase 7, induced therapeutic apoptosis after adenoviral-mediated overexpression. This was observed in vitro in LNCaP and LNCaP-Bcl-2 cells, and in vivo in the prostate of normal mice, which were inoculated with a virus overexpressing caspase-7 under the control of the powerful viral promoter RSV (AvC7). That adenoviral mediated caspase-7 overexpression has the ability to induce therapeutic apoptosis in these two cell lines has now been reported by our group in two papers published in Cancer Research (1, 2). Based on this preliminary data, in aim 1 we proposed to investigate whether adenovirus AvC7 has the ability to modify the natural history of prostate cancer in the TRAMP mouse model, which was developed in the laboratory of Dr. Greenberg at Baylor College of Medicine (3). First generation adenoviral constructs have some potential shortcomings, for instance they are significantly immunogenic, and their ability to maintain expression of the therapeutic gene of interest may be limited to a maximum of 2-3 weeks before they are neutralized by the immune system of the host. In view of this, first generation adenoviruses can only be directly inoculated in a cancerous lesion, and cannot be used systemically to reach metastatic deposits. For this reasons we have proposed in aim 2 to construct a gutless helper-dependent (HD) second-generation adenovirus. As these constructs are completely devoid of proteins of viral origin, they are only minimally immunogenic (4), are not recognized by the immune system, and have the ability to produce the gene of interest up to> 2 years after their initial inoculation (5, 6).
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2002
- Accession Number
- ADA407231
Entities
People
- Marco Marcelli
Organizations
- Baylor College of Medicine