The major goal of this application is to develop a new treatment modality for pulmonary metastasis. Malignant cells usually gain access to the bloodstream through thin-walled venous tumor vessels and grow in solid cores from which fragments or tumor cells may break off to form tumor emboli. Such emboli tend to lodge in the first capillary beds they encounter. Therefore, the lung is a common metastatic side of many human tumors that spread via the hematogenous route. Effective therapy for patients with pulmonary metastases is lacking. To improve the treatment of these lethal sequelae of cancer, the applicant developed a novel tissue-specific gene therapy modality to treat pulmonary metastasis using osteosarcoma as an ideal model system. The objective of this application is to enhance the efficacy of the applicant's tissue-specific gene-therapy approach and develop a novel gene-delivery technique for the treatment of pulmonary metastases. They hypothesis to be tested is: pulmonary metastases can be treated by tissue/tumor-specific promoter-based toxic gene therapy with recombinant adenovirus as a gene delivery vehicle. Treatment efficacy can be enhanced by 1) combining with chemotherapeutic agents, and 2) improving localized delivery of therapeutic agents using an isolated-single-lung-perfusion technique. To test these hypotheses the applicant proposes the following studies. (I) To study the possible benefit of combining gene therapy with chemotherapy, the beneficial effect of four commonly used chemotherapeutic agents, methotrexate, ifosfamide, doxorubicin and cisplatin, on herpes simplex virus thymidine kinase mediated cell- and tumor-kill will be evaluated. The doses of adenovirus, prodrugs, and chemotherapeutic agents for optimal therapeutic efficacy and the sequence of treatment will be studied. (II) To investigate the interaction between toxic gene therapy and chemotherapy, he will study the effect of chemotherapeutic agents on adenovirus mediated transgene expression, the effect of adenoviral gene expression on chemotherapy, and the collaborative efficacy of TK/prodrug and chemotherapeutic agent mediated cell-kill. In particular, the applicant will investigate the potential interference of virus attachment to its receptor and transportation to the nuclei. (III) To increase the local virus concentration and virus-target cell contact time, he will establish an isolated-single-lung-perfusion technique for locoregional delivery of adenovirus and evaluate its therapeutic advantage. He will also evaluate gene transduction efficacy of adenovirus delivered by the isolated-single-lung-perfusion technique.
| Mellon, Matthew J; Ahn, Miwon; Jimenez, Juan A et al. (2008) Anti-angiogenic gene therapy for metastatic renal cell carcinoma produces tumor growth suppression in an athymic nude mouse model. J Urol 179:737-42 |
| Mellon, Matthew J; Bae, Kyung-Hee; Steding, Catherine E et al. (2008) Suppression of renal cell carcinoma growth and metastasis with sustained antiangiogenic gene therapy. Hum Gene Ther 19:487-95 |
| Raikwar, Sudhanshu P; Temm, Constance J; Raikwar, Nandita S et al. (2005) Adenoviral vectors expressing human endostatin-angiostatin and soluble Tie2: enhanced suppression of tumor growth and antiangiogenic effects in a prostate tumor model. Mol Ther 12:1091-100 |
