This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shariat, S. F. Articles by Slawin, K. M. Search for Related Content PubMed PubMed Citation Articles by Shariat, S. F. Articles by Slawin, K. M.

Adenovirus-mediated Transfer of Inducible Caspases

A Novel "Death Switch" Gene Therapeutic Approach to Prostate Cancer¹

The Matsunaga-Conte Prostate Cancer Research Center, Scott Department of Urology [S. F. S., W. S., J. Z., C. N., K. M. S.], Departments of Immunology [S. D., T. K., J. Z., D. M. S.] and Molecular and Cellular Biology [B. A. F., N. G.], Baylor College of Medicine, Houston, Texas 77030

In patients with localized prostate cancer, radical prostatectomy and radiation therapy, although effective in controlling localized disease, are often associated with significant side effects attributable to injury of adjacent tissues. Moreover, patients with metastatic disease eventually fail systemic hormonal or chemotherapy because of the development of progressive, refractory disease. In this study, we evaluated the safety and efficacy of a novel suicide gene therapy that could potentially spare normal tissue while bypassing molecular mechanisms of apoptosis resistance by using chemically inducible effector caspases to trigger apoptosis in prostate cancer cells. Initially, we compared the ability of a panel of inducible Fas signaling intermediates to kill human and murine prostate cancer cell lines. On the basis of the superior killing by downstream caspase-1 and caspase-3, replication-deficient adenoviral vectors expressing conditional caspase-1 (Ad-G/iCasp1) or caspase-3 (Ad-G/iCasp3), regulated by nontoxic, lipid-permeable, chemical inducers of dimerization (CID), were constructed. Upon vector transduction followed by CID administration, aggregation and activation of these recombinant caspases occur, leading to rapid apoptosis. In vitro, both human (LNCaP and PC-3) and murine (TRAMP-C2 and TRAMP-C2G) prostate cancer cell lines were efficiently transduced and killed in a CID-dependent fashion. In vivo, direct injection of Ad-G/iCasp1 into s.c. TRAMP-C2 tumors caused focal but extensive apoptosis without evidence for a bystander effect at the maximal viral dose (i.e., 2.5 x 10¹⁰ viral particles/25 µl) in host animals that also received CID compared with control animals. Treatment with Ad-G/iCasp1 plus CID resulted in a transient, yet significant, reduction both in tumor growth and volume compared with tumors treated with vector but not CID (P < 0.035) or vector-diluent plus CID (P < 0.022), both of which grew more rapidly. These results demonstrate that CID-regulated, caspase-based suicide gene therapy is safe and can inhibit the growth of experimental prostate cancer in vitro and in vivo through potent induction of apoptosis, providing a rationale for further development.

This article has been cited by other articles:

				D. S. Chelur and M. Chalfie From the Cover: Targeted cell killing by reconstituted caspases PNAS, February 13, 2007; 104(7): 2283 - 2288. [Abstract] [Full Text] [PDF]

				J. Chang, M. Xie, V. R. Shah, M. D. Schneider, M. L. Entman, L. Wei, and R. J. Schwartz Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis PNAS, September 26, 2006; 103(39): 14495 - 14500. [Abstract] [Full Text] [PDF]

				M.S. Pinsky, W. Song, Z. Dong, K. Warner, B. Zeitlin, E. Karl, D.E. Hall, and J.E. Nor Activation of iCaspase-9 in Neovessels Inhibits Oral Tumor Progression. J. Dent. Res., May 1, 2006; 85(5): 436 - 441. [Abstract] [Full Text] [PDF]

				U. Fischer and K. Schulze-Osthoff New Approaches and Therapeutics Targeting Apoptosis in Disease Pharmacol. Rev., June 1, 2005; 57(2): 187 - 215. [Abstract] [Full Text] [PDF]

				E. Yu. Nikitina, S. A. Desai, X. Zhao, W. Song, A. Z. Luo, R. D. Gangula, K. M. Slawin, and D. M. Spencer Versatile Prostate Cancer Treatment with Inducible Caspase and Interleukin-12 Cancer Res., May 15, 2005; 65(10): 4309 - 4319. [Abstract] [Full Text] [PDF]

				C. G. Ferreira, M. Epping, F. A. E. Kruyt, and G. Giaccone Apoptosis: Target of Cancer Therapy Clin. Cancer Res., July 1, 2002; 8(7): 2024 - 2034. [Abstract] [Full Text] [PDF]

				X. Xie, X. Zhao, Y. Liu, J. Zhang, R. J. Matusik, K. M. Slawin, and D. M. Spencer Adenovirus-mediated Tissue-targeted Expression of a Caspase-9-based Artificial Death Switch for the Treatment of Prostate Cancer Cancer Res., September 1, 2001; 61(18): 6795 - 6804. [Abstract] [Full Text] [PDF]

				A. F. Gazdar and J. D. Minna Targeted therapies for killing tumor cells PNAS, August 28, 2001; 98(18): 10028 - 10030. [Full Text] [PDF]

				A. A. Mills Changing colors in mice: an inducible system that delivers Genes & Dev., June 15, 2001; 15(12): 1461 - 1467. [Full Text] [PDF]