Abstract
The retinoblastoma gene (RB) is the prototypic tumor suppressor. Studies to date have demonstrated cancer suppression with tumor cells reconstituted with RB ex vivo and implanted into immunodeficient mice, as well as with germline transmission of a human RB transgene into tumor–prone Rb+/− mice. To mimic the therapy of cancer more closely, spontaneous pituitary melanotroph tumors arising in immunocompetent Rb+/− mice were treated with a recombinant adenovirus carrying RB cDNA. Intratumoral RB gene transfer decreased tumor cell proliferation, reestablished innervation by growth–regulatory dopaminergic neurons, inhibited the growth of tumors, and prolonged the life spans of treated animals.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to the full article PDF.
USD 39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Huang, H.-J.S. et al. Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science 242, 1563–1566 (1988).
Riley, D.J., Lee, E.Y.-H.P. & Lee, W.-H. The retinoblastoma protein: More than a tumor suppressor. Annu. Rev. Cell Biol. 10, 1–29 (1994).
Bookstein, R., Shew, J.-Y., Chen, P.-L., Scully, P. & Lee, W.-H. Suppression of the tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene. Science 247, 712–715 (1990).
Madreperla, S.A., Whittum-Hudson, J.A., Prendergast, R.A., Chen, P.-L. & Lee, W.-H. Intraocular tumor suppression of retinoblastoma gene reconstituted retinoblastoma cells. Cancer Res. 61, 6381–6384 (1990).
Ookawa, K. et al. Reconstitution of the retinoblastoma gene suppresses the growth of small cell lung carcinoma cells carrying multiple genetic alterations. Oncogene 8, 2175–2181 (1991)
Goodrich, D.W., Chen, Y., Scully, P. & Lee, W.-H. Expression of the retinoblastoma gene product in bladder carcinoma cells associates with a low frequency of tumor formation. Cancer Res. 52, 1968–1973 (1992).
Wang, N.P., To, H., Lee, W.-H. & Lee, E.Y.-H.P. Tumor suppressor activity of RB and p53 genes in human breast cancer cells. Oncogene 8, 279–288 (1993).
Lee, E.Y.-H.P. et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359, 288–294 (1992).
Jacks, T. et al. Effects of an Rb mutation in the mouse. Nature 359, 295–300 (1992).
Clarke, A.R. et al. Requirement for a functional Rb-1 gene in murine development. Nature 359, 328–330 (1992).
Hu, N. et al. Heterozygous Rb-1δ20/+ mice are predisposed to tumors of the pituitary gland with nearly complete penetrance. Oncogene 9, 1021–1029 (1994).
Williams, B.O. et al. Cooperative tumorigenic effects of germline mutations in Rb and p53 . Nature Genet. 7, 480–484 (1994).
Williams, B.O. et al. Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathologic consequences. EMBO J. 13, 4251–4259 (1994).
Harrison, D.J., Hooper, M.L., Armstrong, J.F. & Clarke, A.R. Effects of heterozygosity for the Rb-1δ19neo allele in the mouse. Oncogene 10, 1615–1620 (1995).
Nikitin, A. & Lee, W.-H. Early loss of the retinoblastoma gene is associated with impaired growth-inhibitory innervation during melanotroph carcinogenesis in Rb+/− mice. Genes Dev. 10, 1870–1879 (1996).
Chang, M.W. et al. Cytostatic therapy for vascular proliferative disorders with a constitutively active form of the retinoblastoma gene product. Science 267, 518–522 (1995).
Bignon, Y.-J. et al. Expression of a retinoblastoma transgene results in dwarf mice. Genes Dev. 7, 1654–1662 (1993).
Chang, C.-Y., Riley, D.J., Lee, E.Y.-H.P. & Lee, W.-H. Quantitative effects of the retinoblastoma gene on mouse development and tissue-specific tumorigenesis. Cell Growth Differ. 4, 1057–1064 (1993).
Mulligan, R.C. The basic science of gene therapy. Science 260, 926–932 (1993).
Goodrich, D.W., Wang, N.P., Qian, Y.-W., Lee, E.Y.-H.P. & Lee, W.-H. The retinoblastoma gene product regulates progression through the Gl phase of the cell cycle. Cell 67, 293–302 (1991).
Hinds, P.W. et al. Regulation of retinoblastoma functions by ectopic expression of human cyclins. Cell 70, 993–1006 (1992).
Lee, E.Y.-H.P. et al. Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation. Genes Dev. 8, 2008–2021 (1994).
Almasan, A. et al. Deficiency of retinoblastoma protein leads to inappropriate S phase entry, activation of E2F-responsive genes, and apoptosis. Proc. Natl. Acad. Sci. USA 92, 5436–5440 (1995).
Hass-Kogan, D.A. et al. Inhibition of apoptosis by the retinoblastoma gene product. EMBO J. 14, 461–472 (1995).
Slark, R.S. et al. Cells differentiating into neuroectoderm undergo apoptosis in the absence of functional retinoblastoma family proteins. J. Cell Biol. 129, 779–788 (1995).
Berry, D.E. et al. Retinoblastoma protein inhibits IFN-g induced apoptosis. Oncogene 12, 1809–1819 (1996).
Falconi, G. & Rossi, G.L. Transauricular hypophysectomy in rats and mice. Endocrinology 74, 301–304 (1964).
Nagatsu, T., Levitt, M. & Udenfriend, S. Tyrosine hydroxylase: The initial step in norepinehrine biosynthesis. J. Biol Chem. 239, 2910–2916 (1964).
Weidenmann, B. & Francke, W.W. Identification and localization of synaptophysin, an integral membrane glycoprotein of M r 38,000 characteristic of presynaptic vesicles. Cell 41, 1017–1028 (1985).
Navone, F. et al. Protein p38: An integral membrane protein specific for small vesicles of neurons and neuroendocrine cells. J. Cell Biol. 103, 2511–2527 (1986).
Sousa, R., Hrinya Tannery, N. & Lafer, E.M. Two new monoclonal antibodies provide immunohistochemical evidence for the unique biochemical similarity of the mouse globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata. Neuroscience 34, 403–410 (1990).
Sousa, R., Hrinya Tannery, N., Zhou, S. & Lafer, E.M. Characterization of a novel synapse protein. I. Developmental expression and cellular localization of the Fl-20 protein and mRNA. J. Neurosci. 12, 2130–2143 (1992).
Russell, E.S. Life span and aging patterns. in Biology of the Laboratory Mouse 2nd edn. (ed. Green, E. L.) 511–519 (McGraw-Hill, New York, 1996).
Zabner, J. et al. Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis. J. Clin. Invest. 97, 1504–1511 (1996).
Roth, J.A. et al. Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer. Nature Med. 2, 985–991 (1996).
Yonish-Rouach, E. et al. Wild-type p53 induces apoptosis of myeloid leukaemia cells that is inhibited by interleukin-6. Nature 352, 345–347 (1991).
Lane, D.P. . p53, guardian of the genome. Nature 358, 15–16 (1992).
Bookstein, R. & Lee, W.-H. Molecular genetics of the retinoblastoma suppressor gene. Crit. Rev. Oncogen. 2, 211–227 (1991).
Harbour, J.W. et al. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 241, 353–357 (1988).
Hensel, C.H. et al. Altered structure and expression of the human retinoblastoma susceptibility gene in small cell lung cancer. Cancer Res. 50, 3067–3072 (1990).
Shizmu, E. et al. RB protein status and clinical correlation for 171 cell lines representing lung cancer, extrapulmonary small cell carcinoma, and mesothelioma. Oncogene 9, 2441–2448 (1994).
Pack, R.J. & Widdecomb, J.G. Amine-containing cells of the lung. Eur. J. Respir. Dis. 65, 559–578 (1984).
Rich, D.P. et al. Development and analysis of recombinant adenoviruses for gene therapy of cystic fibrosis. Hum. Gene Ther. 4, 461–476 (1993).
Jones, N. & Shenck, T. Isolation of adenovirus type 5 host range deletion mutants defective for transformation of rat embryo cells. Cell 17, 683–689 (1979).
Hong, F.D. et al. Structure of the human retinoblastoma gene. Proc. Natl. Acad. Sci. USA 86, 5502–5506 (1989).
Durfee, T. et al. The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. Genes Dev. 7, 555–569 (1993).
Bonnerot, C. & Nicolas, J.-F. Application of LacZ fusions to post implantation development. Methods Enzymol. 225, 451–469 (1993).
Gavrieli, Y., Sherman, Y. & Ben-Sasson, S.A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 119, 493–507 (1992).
Huang, S., Wang, N.P., Tseng, B.Y., Lee, W.-H. & Lee, E.Y.-H.P. Two distinct and frequently mutated regions of the retinoblastoma protein are required for binding to SV40 T antigen. EMBO J. 9, 1815–1822 (1990).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Riley, D., Nikitin, A. & Lee, WH. Adenovirus–mediated retinoblastoma gene therapy suppresses spontaneous pituitary melanotroph tumors in Rb+/− mice. Nat Med 2, 1316–1321 (1996). https://doi.org/10.1038/nm1296-1316
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1038/nm1296-1316
This article is cited by
-
p21 suppresses inflammation and tumorigenesis on pRB-deficient stratified epithelia
Oncogene (2014)
-
Mechanisms of Disease: the pathogenesis of pituitary tumors
Nature Clinical Practice Endocrinology & Metabolism (2006)
-
The pathogenesis of pituitary tumours
Nature Reviews Cancer (2002)
-
Cancer gene therapy: fringe or cutting edge?
Nature Reviews Cancer (2001)
-
Gene therapy for brain tumors
Current Oncology Reports (2000)
