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Liposomal vector mediated delivery of the 3p FUS1 gene demonstrates potent antitumor activity against human lung cancer in vivo

Cancer Gene Therapy volume 11, pages 733–739 (2004)Cite this article

Abstract

Lung cancer is one of the leading causes of death in the world. The underlying cause for lung cancer has been attributed to various factors that include alteration and mutation in the tumor suppressor genes. Restoration of normal function of the tumor suppressor gene is a potential therapeutic strategy. Recent studies have identified a group of candidate tumor suppressor genes on human chromosome 3p21.3 that are frequently deleted in human lung and breast cancers. Among the various genes identified in the 3p21.3 region, we tested the antitumor activity of the FUS1 gene in two human non-small-cell lung cancer (NSCLC) xenografts in vivo. Intratumoral administration of FUS1 gene complexed to DOTAP:cholesterol (DOTAP:Chol) liposome into subcutaneous H1299 and A549 lung tumor xenograft resulted in significant (P=.02) inhibition of tumor growth. Furthermore, intravenous injections of DOTAP:Chol–FUS1 complex into mice bearing experimental A549 lung metastasis demonstrated significant (P=.001) decrease in the number of metastatic tumor nodules. Finally, lung tumor-bearing animals when treated with DOTAP:Chol–FUS1 complex demonstrate prolonged survival (median survival time: 80 days, P=.01) compared to control animals. This result demonstrates the potent tumor suppressive activity of the FUS1 gene and is a promising therapeutic agent for treatment of primary and disseminated human lung cancer.

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References

  1. Carbone DA, Minna JD . In vivo gene therapy of human lung cancer using wild-type p53 delivered by retrovirus. J Natl Cancer Inst. 1994;86:1437–1438.

    Article  CAS  PubMed  Google Scholar 

  2. Hansen HH, Rørth M . Lung cancer. Caner Chemother Biol Response Mod. 1999;18:336–356.

    CAS  Google Scholar 

  3. Hoffman PC, Mauer AM, Vokes EE . Lung cancer. Lancet. 2000;355:479–485.

    Article  CAS  PubMed  Google Scholar 

  4. Park BJ, Louie O, Altorki N . Staging and the surgical management of lung cancer. Radiol Clin North Am. 2000;38:545–561.

    Article  CAS  PubMed  Google Scholar 

  5. Bunn PA, Soriano A, Johnson G, Heasley L . New therapeutic strategies for lung cancer: biology and molecular biology come of age. Chest. 2000;117:163S–168S.

    Article  CAS  PubMed  Google Scholar 

  6. Zochbauer-Muller S, Gazdar AF, Minna JD . Molecular pathogenesis of lung cancer. Ann Rev Physiol. 2002;64:681–708.

    Article  CAS  Google Scholar 

  7. Gazdar A, Roth JA, Minna JD . Focus on lung cancer. Cancer Cell. 2002;1:49–52.

    Article  PubMed  Google Scholar 

  8. Wistuba II, Behrens C, Virmani AK, et al. High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res. 2000;60:1949–1960.

    CAS  PubMed  Google Scholar 

  9. Girard L, Zochbauer-Muller S, Virmani AK, Gazdar AF, Minna JD . Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. Cancer Res. 2000;60:4894–4906.

    CAS  PubMed  Google Scholar 

  10. Maitra A, Wistuba II, Washington C, et al. High-resolution chromosome 3p allelotyping of breast carcinomas and precursor lesions demonstrates frequent loss of heterozygosity and a discontinuous pattern of allele loss. Am J Pathol. 2001;159:119–130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lerman MI, Minna JD . The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. Cancer Res. 2000;60:6116–6133.

    CAS  PubMed  Google Scholar 

  12. Sekido Y, Ahmadian M, Wistuba II, et al. Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene. Oncogene. 1998;16:3151–3157.

    Article  CAS  PubMed  Google Scholar 

  13. Kondo M, Ji L, Kamibayashi C, Tomizawa Y, et al. Overexpression of candidate tumor suppressor gene FUS1 isolated from the 3p21.3 homozygous deletion region leads to G1 arrest and growth inhibition of lung cancer cells. Oncogene. 2001;20:6258–6262.

    Article  CAS  PubMed  Google Scholar 

  14. Ji L, Nishizaki M, Gao B, et al. Expression of several genes in the human chromosome 3p21.3 homozygous deletion region by an adenovirus vector results in tumor suppressor activities in vitro and in vivo. Cancer Res. 2002;62:2715–2720.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Uno F, Sasaki I, Nishizaki M, et al. Myristolyation of Fus1 protein is required for tumor suppression in human lung cancer cells. Cancer Res. 2004;64:2969–2976.

    Article  CAS  PubMed  Google Scholar 

  16. Templeton NS, Lasic DD, Frederik PM, et al. Improved DNA:liposome complexes for increased systemic delivery and gene expression. Nat Biotechnol. 1997;15:647–652.

    Article  CAS  PubMed  Google Scholar 

  17. Ramesh R, Saeki T, Templeton NS, et al. Successful treatment of primary and disseminated lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector. Mol Ther. 2001;3:337–350.

    Article  CAS  PubMed  Google Scholar 

  18. Ito I, Began G, Mohiuddin I, et al. Increased uptake of liposomal–DNA complexes by lung metastases follow-ing intravenous administration. Mol Ther. 2003;7:409–418.

    Article  CAS  PubMed  Google Scholar 

  19. Saeki T, Mhashilkar A, Swanson X, et al. Inhibition of lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo. Oncogene. 2002;21:4558–4566.

    Article  CAS  PubMed  Google Scholar 

  20. Li S, Rizzo MA, Bhattacharya S, Huang L . Characterization of cationic lipid-protamine-DNA (LPD) complexes for intravenous gene delivery. Gene Therapy. 1998;5:930–997.

    Article  CAS  PubMed  Google Scholar 

  21. Tan Y, Li S, Pitt BR, Huang L . The inhibitory role of CpG immunostimulatory motifs in cationic lipid vector mediated transgene expression in vivo. Hum Gene Ther. 1999;10:2153–2161.

    Article  CAS  PubMed  Google Scholar 

  22. Dow SW, Fradkin LG, Liggitt DH, et al. Lipid–DNA complexes induce potent activation of innate immune responses and antitumor activity when administered intravenously. J Immunol. 1999;163:1552–1561.

    CAS  PubMed  Google Scholar 

  23. Ito I, Saeki T, Mohiuddin I, et al. Persistent transgene expression following intravenous administration of a liposomal complex: role of IL-10 mediated immune suppression. Mol Ther. 2004;9:318–327.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Nora Rios for assistance in preparation of the manuscript. This work was supported in part by Public Health Service Grant P01 CA78778-01A1 (JAR), by the Specialized Program of Research Excellence (SPORE) in Lung Cancer 2P50-CA70970-04 (JDM and JAR); by a Career Development Award P50-CA70907-5 (RR); by gifts to the Division of Surgery, from Tenneco and Exxon for the Core Laboratory Facility; by the UT MD Anderson Cancer Center Support Core Grant CA 16672; by the Texas Tobacco Settlement Fund as appropriated by the Texas State Legislature (Project 8), by the MD Anderson WM Keck Center for Cancer Gene Therapy (JR, RR), by Texas Higher Education Coordinating Board ATP/ARP Grant 003657-0078-2001 (RR); by BESCT Lung Cancer Program grant DAMD17-01-1-0689 (LJ, RR); by TARGET Lung Cancer Grant DAMD17-02-1-0706 [LJ, RR]; by Cancer Center Support (CORE) Grant CA 16672; and by a sponsored research agreement with Introgen Therapeutics, Inc.

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Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, Section of Thoracic Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA

    Isao Ito, Lin Ji, Fumihiro Tanaka, Yuji Saito, Began Gopalan, Cynthia D Branch, Kai Xu, Jack A Roth & Rajagopal Ramesh

  2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA

    E Neely Atkinson & Benjamin N Bekele

  3. Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA

    L Clifton Stephens

  4. Department of Internal Medicine and Pharmacology, Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    John D Minna

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  1. Isao Ito
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  3. Fumihiro Tanaka
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  11. John D Minna
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  13. Rajagopal Ramesh
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Correspondence to Rajagopal Ramesh.

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Ito, I., Ji, L., Tanaka, F. et al. Liposomal vector mediated delivery of the 3p FUS1 gene demonstrates potent antitumor activity against human lung cancer in vivo. Cancer Gene Ther 11, 733–739 (2004). https://doi.org/10.1038/sj.cgt.7700756

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