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Ribozyme targeting of the growth factor pleiotrophin in established tumors: a gene therapy approach

Gene Therapy volume 12, pages 339–346 (2005)Cite this article

Abstract

The growth and metastasis of solid tumors relies on the activities of polypeptide growth factors to recruit stromal tissue and expand the tumor mass. Pleiotrophin (PTN) is a secreted growth factor with angiogenic activity that has been found to contribute to the growth and metastasis of tumors including melanoma. Here, we present a gene therapy approach of targeting PTN in established tumors using ribozymes. Tetracycline-regulated ribozyme expression vectors were used to deplete conditionally PTN mRNA from melanoma xenograft tumors in vivo. We found that tetracycline-mediated initiation of ribozyme expression in established tumors reduced further tumor growth. Next, we generated synthetic anti-PTN ribozymes that inhibit PTN-dependent colony formation of cells in soft agar. Intraperitoneal administration of these synthetic ribozymes into nude mice inhibited growth of PTN-positive, subcutaneous melanoma. Furthermore, PTN released from the tumors into the circulation of mice was reduced after ribozyme treatment. These data show that ribozyme targeting of rate-limiting tumor growth factors could provide an efficient tool for cancer therapy and that the efficacy may be reflected in the reduction of the serum levels of the targeted protein, PTN.

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Acknowledgements

We thank Dr SG Downing, A Murray and A Wüstenhagen for help with experiments. Drs A Aigner, HJ List (Georgetown University), P Pavco (RPI) and M Herlyn (Wistar Institute, Philadelphia) discussed the data and made helpful suggestions. Dr M Herlyn also kindly provided the 1205LU melanoma cell line and Dr M Vigny (INSERM, Paris, France) the 4B7 mouse monoclonal antibody. The studies were supported by grants from the NIH/National Cancer Institute to AW.

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Author notes

  1. C Malerczyk

    Present address: Chiron-Behring, Marburg, Germany

  2. A M Schulte

    Present address: Aventis, Frankfurt/M, Germany

  3. F Czubayko

    Present address: Department of Pharmacology, Philipps-University Marburg, Germany

  4. C Malerczyk and A M Schulte: These authors contributed equally to this work

Authors and Affiliations

  1. Lombardi Cancer Center, Georgetown University, Washington, DC, USA

    C Malerczyk, A M Schulte, F Czubayko, A T Riegel & A Wellstein

  2. Ribozyme Pharmaceuticals Inc., Boulder, CO, USA

    L Bellon & D Macejak

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  1. C Malerczyk
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Malerczyk, C., Schulte, A., Czubayko, F. et al. Ribozyme targeting of the growth factor pleiotrophin in established tumors: a gene therapy approach. Gene Ther 12, 339–346 (2005). https://doi.org/10.1038/sj.gt.3302398

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