It is important to develop additional therapeutic approaches for prostate cancer which can be applied separately or in conjunction with current modalities. Various strategies for gene therapy may provide therapeutic benefits for this important disease. The mouse prostate reconstitution (MPR) model system can be used as a preclinical model for gene therapy in prostate cancer. The validity of thi in vivo model for prostate cancer is well established and its unique features provide an opportunity to test important parameters of specific gene therapy protocols including; general efficacy; appropriate timing o therapy; as well s the comparative efficiency of various delivery systems. We have tested a replication- defective recombinant adenovirus carrying the Herpes Simplex Virus thymidine kinase (HSV-tk) gene followed by grancicylovir (GCV) in vivo and in vivo using cell lines derived from a ras + myc=induced mouse prostate carcinoma as well as from human prostate-cancer. Following inoculation of the mouse prostate cancer line cell into immunocompetent male hosts, we found that subcutaneous tumors in treated animals (n=5) were reduced in volume to 18% that in untreated animals (n-15). On histologic evaluation athe treated tumors demonstrated significantly higher levels of apoptosis and necrosis than control tumors. The efficacy of HSV-tk gene therapy was further demonstrated using the C57BL/6 MPR carcinogenesis model. Primary site lesions were injected with Ad/HSV-tk virus and the virus and the mice were treated with GCV for 6 days. In the control group (n=5), 4 of the MPRs produced poorly differentiated carcinomas (wt= 939 + 875 mg) and ! was hyperplastic (wt=77 mg). In the treated group (n-5), although malignant cells were present, extensive necrosis and growth suppression was apparent in all cases (wt+19 + 3 mg). These results demonstrate the efficacy of HSV-tk/GCV gene therapy as well as the utility of the MPR model system as a preclinical model. The metastatic MPR model using p53 knock-out mice allows extension of these studies to all aspects of clinically relevant disease. The primary site lesion, under the renal capsule, is suitable for injection of gene therapy vectors as we have done with Ad(HSV-tk and systemic factors which influence metastasis can be evaluated. The parameters we will evaluate include overall growth response of the primary tumor, number and location of metastases, apoptotic response, and development of an immune response by evaluating activation of tumor infiltrating lymphocytes as well as by evaluating the ability to reject subsequent challenge with tumor cells. We propose to use these preclinical models to test genes involved in growth suppression (e.g.,p53 and p21) a well as genes which may enhance the localized immune response (e.g., IL-2 and GM-CSF) together with in HSV-tk/GCV gene therapy protocol. The efficacy of the combination of gene therapy with anti-androgen therapy or radiothermy will also be evaluated. Phase I clinical trials will be developed for a select groups of patient based on the results of preclinical trials and after vector safety has been established.
Showing the most recent 10 out of 262 publications
