acyclovir and Neoplasm-Metastasis

Delivery of therapeutic toxic genes to and their expression in tumor cells through the use of tissue-specific promoters could decrease their toxic effect on neighboring normal cells when virus-mediated gene delivery results in their infection. We have demonstrated the utility of two prostate cancer-specific promoters, long PSA and osteocalcin, for tissue-specific toxic gene therapy for prostate cancer. The two promoters were highly active in both androgen-dependent and androgen-independent prostate cancer cells. We also introduce the Phase I trial of osteocalcin promoter-based toxic gene therapy for bone metastases of prostate cancer, which is in progress at the University of Virginia.

Topics: Acyclovir; Animals; Clinical Trials, Phase I as Topic; Genetic Therapy; Humans; Male; Neoplasm Metastasis; Osteocalcin; Osteosarcoma; Promoter Regions, Genetic; Prostate-Specific Antigen; Prostatic Neoplasms

Neurological disorders and conditions affecting the maxillofacial region result in disabilities that affect an individual's functioning. Sensory or motor disturbances of the nerves may be caused by trauma, infections, pressure effect or infiltration by tumours or other health conditions. Two rare cases of nerve afflictions are described here with their typical clinical features. The first case had an involvement of maxillary, mandibular and ophthalmic divisions of the trigeminal nerve (sensory) due to herpes zoster infection in a very young patient and the second case had a unilateral isolated hypoglossal nerve palsy (motor) secondary to infiltration of the nerve by carcinoma of pyriform fossa.

Topics: Acyclovir; Adolescent; Adult; Antiviral Agents; Cranial Nerve Neoplasms; Head and Neck Neoplasms; Herpes Zoster; Humans; Hypoglossal Nerve Diseases; Male; Neoplasm Metastasis; Pyriform Sinus; Tongue Diseases; Trigeminal Nerve Diseases

The herpes simplex virus (HSV) thymidine kinase gene (tk) forms the basis of a widely used strategy for suicide gene therapy. A library of HSV thymidine kinase enzyme (TK) active site mutants having different affinities for guanosine analog prodrugs was developed. We sought to determine the optimal combination of tk variant and prodrug specifically for prostate cancer gene therapy, using in vitro and in vivo studies of adenovirally infected CL1, DU-145, and LNCaP tumor lines carrying wild-type tk, tk30, tk75, and sr39tk mutants expressed by a strong, constitutive cytomegalovirus promoter and treated with ganciclovir and acyclovir. In vitro experiments involving prostate cancer (CaP) cell line infection were carried out with a broad range of prodrug concentrations, and cell killing was determined by limiting dilution (colony-forming), MTT, and propidium iodide assays. In vivo studies based on CL1-GFP xenograft experiments were carried out to examine the ability of each TK variant to prevent tumor formation and to inhibit tumor growth and development of metastases in established orthotopic and subcutaneous tumors in SCID mice. Both in vitro and in vivo studies suggest improved killing with the sr39tk variant. Thus, the results suggest that the use of sr39tk in future trials of prostate cancer tk suicide gene therapy may be beneficial.

Topics: Acyclovir; Animals; Antiviral Agents; Apoptosis; Binding Sites; Blotting, Southern; Blotting, Western; Disease Progression; Dose-Response Relationship, Drug; Flow Cytometry; Ganciclovir; Genetic Therapy; Green Fluorescent Proteins; Guanosine; Humans; Luminescent Proteins; Male; Mice; Mice, SCID; Mutation; Neoplasm Metastasis; Neoplasm Transplantation; Prodrugs; Propidium; Prostatic Neoplasms; Simplexvirus; Tetrazolium Salts; Thiazoles; Thymidine Kinase; Tomography, Emission-Computed; Tumor Cells, Cultured