Two impediments which limit the effectiveness of conventional cancer treatment are the lack of a significant differential response between normal and tumor tissue and the development of biochemical resistance to commonly used therapies. Recent evidence suggests that the latter limitation is determined, in part, by the genetic makeup of the tumor cell. This research proposal will examine the general hypothesis that the therapeutic index of cancer radiotherapy can be enhanced by employed suicide gene therapy as an adjuvant therapy and by manipulating the p53 status of the tumor cell. Recombinant retroviruses encoding a novel E. Coli cytosine deaminase (CD)/Herpes Simplex Virus thymidine kinase (HSV-1TK) fusion gene have been generated and used to express the CD/HSV-1 TK fusion protein in tumor cells. We will test hypothesis that these two suicide gene systems, when combined, function synergistically to kill tumor cells in vivo. Based on our previous observations that each suicide gene system independently can radiosensitize tumor cells in vitro, we will test the hypothesis that expression of the CD/HSV-1 TK fusion protein will result in tumor radiosensitization in vivo. Because recent studies have indicated that the efficacy of chemotherapy and radiotherapy is dependent on tumor p53 status, we will test the hypothesis that co-expression of wild-type p53 will increase the effectiveness of the combined suicide gene therapy/radiotherapy approach. Recombinant adenoviruses will be used to deliver the CD/HSV-1 TK fusion and p53 genes to tumor cells I vivo. We will test the hypothesis that this multifaceted approach will be more efficacious at tumor control than either suicide gene therapy or radiotherapy alone. As improvements in locoregional control of tumor could translate into better survival outcomes, this research may provide the rationale upon which future clinical trials using this multifaceted approach will be based.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075456-03
Application #
2896164
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
1997-08-01
Project End
2000-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Henry Ford Health System
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Barton, Kenneth N; Xia, Xueqing; Yan, Hui et al. (2004) A quantitative method for measuring gene expression magnitude and volume delivered by gene therapy vectors. Mol Ther 9:625-31
Barton, Kenneth N; Tyson, Donald; Stricker, Hans et al. (2003) GENIS: gene expression of sodium iodide symporter for noninvasive imaging of gene therapy vectors and quantification of gene expression in vivo. Mol Ther 8:508-18
Freytag, Svend O; Stricker, Hans; Pegg, Jan et al. (2003) Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer. Cancer Res 63:7497-506
Freytag, Svend O; Khil, Mark; Stricker, Hans et al. (2002) Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res 62:4968-76
Freytag, Svend O; Paielli, Dell; Wing, Mark et al. (2002) Efficacy and toxicity of replication-competent adenovirus-mediated double suicide gene therapy in combination with radiation therapy in an orthotopic mouse prostate cancer model. Int J Radiat Oncol Biol Phys 54:873-85
Paielli, D L; Wing, M S; Rogulski, K R et al. (2000) Evaluation of the biodistribution, persistence, toxicity, and potential of germ-line transmission of a replication-competent human adenovirus following intraprostatic administration in the mouse. Mol Ther 1:263-74
Rogulski, K R; Freytag, S O; Zhang, K et al. (2000) In vivo antitumor activity of ONYX-015 is influenced by p53 status and is augmented by radiotherapy. Cancer Res 60:1193-6
Rogulski, K R; Wing, M S; Paielli, D L et al. (2000) Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization. Hum Gene Ther 11:67-76
Xie, Y; Gilbert, J D; Kim, J H et al. (1999) Efficacy of adenovirus-mediated CD/5-FC and HSV-1 thymidine kinase/ganciclovir suicide gene therapies concomitant with p53 gene therapy. Clin Cancer Res 5:4224-32
Freytag, S O; Rogulski, K R; Paielli, D L et al. (1998) A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy. Hum Gene Ther 9:1323-33