Clinical Cancer Research, Vol 3, Issue 11 2081-2088, Copyright © 1997 by American Association for Cancer Research

ARTICLES

Pronounced antitumor effects and tumor radiosensitization of double suicide gene therapy

KR Rogulski, K Zhang, A Kolozsvary, JH Kim and SO Freytag
Departments of Radiation Oncology and Molecular Biology, Henry Ford Health System, Detroit, Michigan 48202-4689, USA.

The efficacy of HSV-1 thymidine kinase (TK) and Escherichia coli cytosine deaminase (CD) suicide gene therapies as cancer treatments are currently being examined in humans. We demonstrated previously that compared to single suicide gene therapy, greater levels of targeted cytotoxicity and radiosensitization can be achieved in vitro by genetically modifying tumor cells to express CD and HSV-1 TK concomitantly, as a fusion protein. In the present study, the efficacy of the combined double suicide gene therapy/radiotherapy approach was examined in vivo. Nude mice were injected either s.c. or i.m. with 9L gliosarcoma cells expressing an E. coli CD/HSV-1 TK fusion gene. Double suicide gene therapy using 5-fluorocytosine (500 mg/kg) and ganciclovir (30 mg/kg) proved to be markedly better at delaying tumor growth and achieving a tumor cure than single suicide gene therapy, which used 5-fluorocytosine or ganciclovir administered independently. Importantly, double suicide gene therapy was highly effective against large experimental tumors (>2 cm3), reducing tumor volume an average of 99% and producing a 40% tumor cure. Moreover, double suicide gene therapy profoundly potentiated the antitumor effects of radiation. The results indicate that double suicide gene therapy, particularly when coupled with radiotherapy, may represent a highly effective means of eradicating tumors.

This article has been cited by other articles:

				C. Li, M.-F. Penet, P. Winnard Jr., D. Artemov, and Z. M. Bhujwalla Image-Guided Enzyme/Prodrug Cancer Therapy Clin. Cancer Res., January 15, 2008; 14(2): 515 - 522. [Abstract] [Full Text] [PDF]

				S. J. Advani, R. R. Weichselbaum, and S. J. Chmura Enhancing Radiotherapy With Genetically Engineered Viruses J. Clin. Oncol., September 10, 2007; 25(26): 4090 - 4095. [Abstract] [Full Text] [PDF]

				S. O. Freytag, H. Stricker, J. Pegg, D. Paielli, D. G. Pradhan, J. Peabody, M. DePeralta-Venturina, X. Xia, S. Brown, M. Lu, et al. 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., November 1, 2003; 63(21): 7497 - 7506. [Abstract] [Full Text] [PDF]

				S. O. Freytag, M. Khil, H. Stricker, J. Peabody, M. Menon, M. DePeralta-Venturina, D. Nafziger, J. Pegg, D. Paielli, S. Brown, et al. Phase I Study of Replication-competent Adenovirus-mediated Double Suicide Gene Therapy for the Treatment of Locally Recurrent Prostate Cancer Cancer Res., September 1, 2002; 62(17): 4968 - 4976. [Abstract] [Full Text] [PDF]

				C. R. Miller, C. R. Williams, D. J. Buchsbaum, and G. Y. Gillespie Intratumoral 5-Fluorouracil Produced by Cytosine Deaminase/5-Fluorocytosine Gene Therapy Is Effective for Experimental Human Glioblastomas Cancer Res., February 1, 2002; 62(3): 773 - 780. [Abstract] [Full Text] [PDF]

				E. Kievit, M. K. Nyati, E. Ng, L. D. Stegman, J. Parsels, B. D. Ross, A. Rehemtulla, and T. S. Lawrence Yeast Cytosine Deaminase Improves Radiosensitization and Bystander Effect by 5-Fluorocytosine of Human Colorectal Cancer Xenografts Cancer Res., December 1, 2000; 60(23): 6649 - 6655. [Abstract] [Full Text]

				K. R. Rogulski, S. O. Freytag, K. Zhang, J. D. Gilbert, D. L. Paielli, J. H. Kim, C. C. Heise, and D. H. Kirn In Vivo Antitumor Activity of ONYX-015 Is Influenced by p53 Status and Is Augmented by Radiotherapy Cancer Res., March 1, 2000; 60(5): 1193 - 1196. [Abstract] [Full Text]

				Y. Xie, J. D. Gilbert, J. H. Kim, and S. O. Freytag Efficacy of Adenovirus-mediated CD/5-FC and HSV-1 Thymidine Kinase/Ganciclovir Suicide Gene Therapies Concomitant with p53 Gene Therapy Clin. Cancer Res., December 1, 1999; 5(12): 4224 - 4232. [Abstract] [Full Text] [PDF]

				E. Kievit, E. Bershad, E. Ng, P. Sethna, I. Dev, T. S. Lawrence, and A. Rehemtulla Superiority of Yeast over Bacterial Cytosine Deaminase for Enzyme/Prodrug Gene Therapy in Colon Cancer Xenografts Cancer Res., April 1, 1999; 59(7): 1417 - 1421. [Abstract] [Full Text] [PDF]