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 Lopez, M. V. Articles by Podhajcer, O. L. Search for Related Content PubMed PubMed Citation Articles by Lopez, M. V. Articles by Podhajcer, O. L.

Research Articles: Therapeutics, Targets, and Development

Expression of a suicidal gene under control of the human secreted protein acidic and rich in cysteine (SPARC) promoter in tumor or stromal cells led to the inhibition of tumor cell growth

¹ Gene Therapy Laboratory, Leloir Institute-Consejo Nacional de Investigaciones Científicas y Técnicas, Faculty of Exact and Natural Sciences, University of Buenos Aires; ² Centro Nacional de Genética Médica (Administración Nacional de Laboratorios e Institutos de Salud Carlos G. Malbrán), Buenos Aires, Argentina; ³ Faculty of Veterinary Sciences, University of La Plata, La Plata, Argentina; and ⁴ Bone and Joint Research Unit, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, Charterhouse Square, London, United Kingdom

Requests for reprints: Osvaldo L. Podhajcer, Fundacion Instituto Leloir, Avenida Patricias Argentinas 435, (1405) Buenos Aires, Argentina. Phone: 54-11-5238-7500, ext. 3107; Fax: 54-11-5238-7501. E-mail: opodhajcer{at}leloir.org.ar

Abstract

The successful use of transcriptional targeting for cancer therapy depends on the activity of a given promoter inside the malignant cell. Because solid human tumors evolve as a "cross-talk" between the different cell types within the tumor, we hypothesized that targeting the entire tumor mass might have better therapeutic effect. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein overexpressed in different human cancers malignant melanomas both in the malignant cells compartment as in the stromal one (fibroblasts and endothelial cells). We have shown that expression of the herpes simplex virus–thymidine kinase (TK) gene driven by the SPARC promoter in combination with ganciclovir inhibited human melanoma cell growth in monolayer as well as in multicellular spheroids. This inhibitory effect was observed both in homotypic spheroids composed of melanoma cells alone as well as in spheroids made of melanoma cells and stromal cells. Expression of the TK gene was also efficient to inhibit the in vivo tumor growth of established melanomas when TK was expressed either by the malignant cells themselves or by coadministered endothelial cells. Our data suggest that the use of therapeutic genes driven by SPARC promoter could be a valuable strategy for cancer therapy aiming to target all the cellular components of the tumor mass. [Mol Cancer Ther 2006;5(10):2503–11]

Grant support: Welcome Trust, United Kingdom, the René Barón and Amigos de la Fundación Leloir para la Investigación contra el Cáncer Foundations, The National Ministry of Health and the National Agency for Promotion of Science and Technology, Argentina, and the Arthritis Research Campaign, United Kingdom.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: M.V. Lopez and P. Blanco contributed equally to this work and should both be considered first authors.

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 5/17/06; revised 7/17/06; accepted 8/25/06.

This article has been cited by other articles:

				A. G. Bharadwaj, K. Rector, and M. A. Simpson Inducible Hyaluronan Production Reveals Differential Effects on Prostate Tumor Cell Growth and Tumor Angiogenesis J. Biol. Chem., July 13, 2007; 282(28): 20561 - 20572. [Abstract] [Full Text] [PDF]