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. 1995 Nov 21;92(24):11024–11028. doi: 10.1073/pnas.92.24.11024

A recombinant bcl-x s adenovirus selectively induces apoptosis in cancer cells but not in normal bone marrow cells.

M F Clarke 1, I J Apel 1, M A Benedict 1, P G Eipers 1, V Sumantran 1, M González-García 1, M Doedens 1, N Fukunaga 1, B Davidson 1, J E Dick 1, et al.
PMCID: PMC40563  PMID: 7479929

Abstract

Many cancers overexpress a member of the bcl-2 family of inhibitors of apoptosis. To determine the role of these proteins in maintaining cancer cell viability, an adenovirus vector that expresses bcl-xs, a functional inhibitor of these proteins, was constructed. Even in the absence of an exogenous apoptotic signal such as x-irradiation, this virus specifically and efficiently kills carcinoma cells arising from multiple organs including breast, colon, stomach, and neuroblasts. In contrast, normal hematopoietic progenitor cells and primitive cells capable of repopulating severe combined immunodeficient mice were refractory to killing by the bcl-xs adenovirus. These results suggest that Bcl-2 family members are required for survival of cancer cells derived from solid tissues. The bcl-xs adenovirus vector may prove useful in killing cancer cells contaminating the bone marrow of patients undergoing autologous bone marrow transplantation.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Askew D. S., Ihle J. N., Cleveland J. L. Activation of apoptosis associated with enforced myc expression in myeloid progenitor cells is dominant to the suppression of apoptosis by interleukin-3 or erythropoietin. Blood. 1993 Oct 1;82(7):2079–2087. [PubMed] [Google Scholar]
  2. Boise L. H., González-García M., Postema C. E., Ding L., Lindsten T., Turka L. A., Mao X., Nuñez G., Thompson C. B. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993 Aug 27;74(4):597–608. doi: 10.1016/0092-8674(93)90508-n. [DOI] [PubMed] [Google Scholar]
  3. Brenner M. K., Rill D. R., Moen R. C., Krance R. A., Mirro J., Jr, Anderson W. F., Ihle J. N. Gene-marking to trace origin of relapse after autologous bone-marrow transplantation. Lancet. 1993 Jan 9;341(8837):85–86. doi: 10.1016/0140-6736(93)92560-g. [DOI] [PubMed] [Google Scholar]
  4. Campos L., Rouault J. P., Sabido O., Oriol P., Roubi N., Vasselon C., Archimbaud E., Magaud J. P., Guyotat D. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood. 1993 Jun 1;81(11):3091–3096. [PubMed] [Google Scholar]
  5. Castle V. P., Heidelberger K. P., Bromberg J., Ou X., Dole M., Nuñez G. Expression of the apoptosis-suppressing protein bcl-2, in neuroblastoma is associated with unfavorable histology and N-myc amplification. Am J Pathol. 1993 Dec;143(6):1543–1550. [PMC free article] [PubMed] [Google Scholar]
  6. Cotten M., Wagner E., Zatloukal K., Birnstiel M. L. Chicken adenovirus (CELO virus) particles augment receptor-mediated DNA delivery to mammalian cells and yield exceptional levels of stable transformants. J Virol. 1993 Jul;67(7):3777–3785. doi: 10.1128/jvi.67.7.3777-3785.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cotten M., Wagner E., Zatloukal K., Phillips S., Curiel D. T., Birnstiel M. L. High-efficiency receptor-mediated delivery of small and large (48 kilobase gene constructs using the endosome-disruption activity of defective or chemically inactivated adenovirus particles. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6094–6098. doi: 10.1073/pnas.89.13.6094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Evan G. I., Wyllie A. H., Gilbert C. S., Littlewood T. D., Land H., Brooks M., Waters C. M., Penn L. Z., Hancock D. C. Induction of apoptosis in fibroblasts by c-myc protein. Cell. 1992 Apr 3;69(1):119–128. doi: 10.1016/0092-8674(92)90123-t. [DOI] [PubMed] [Google Scholar]
  9. 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. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ghosh-Choudhury G., Haj-Ahmad Y., Brinkley P., Rudy J., Graham F. L. Human adenovirus cloning vectors based on infectious bacterial plasmids. Gene. 1986;50(1-3):161–171. doi: 10.1016/0378-1119(86)90321-5. [DOI] [PubMed] [Google Scholar]
  11. González-García M., Pérez-Ballestero R., Ding L., Duan L., Boise L. H., Thompson C. B., Núez G. bcl-XL is the major bcl-x mRNA form expressed during murine development and its product localizes to mitochondria. Development. 1994 Oct;120(10):3033–3042. doi: 10.1242/dev.120.10.3033. [DOI] [PubMed] [Google Scholar]
  12. Gottschalk A. R., Boise L. H., Thompson C. B., Quintáns J. Identification of immunosuppressant-induced apoptosis in a murine B-cell line and its prevention by bcl-x but not bcl-2. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7350–7354. doi: 10.1073/pnas.91.15.7350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Grubb B. R., Pickles R. J., Ye H., Yankaskas J. R., Vick R. N., Engelhardt J. F., Wilson J. M., Johnson L. G., Boucher R. C. Inefficient gene transfer by adenovirus vector to cystic fibrosis airway epithelia of mice and humans. Nature. 1994 Oct 27;371(6500):802–806. doi: 10.1038/371802a0. [DOI] [PubMed] [Google Scholar]
  14. Head D. R., Kennedy P. S., Goyette R. E. Metastatic neuroblastoma in bone marrow aspirate smears. Am J Clin Pathol. 1979 Dec;72(6):1008–1011. doi: 10.1093/ajcp/72.6.1008. [DOI] [PubMed] [Google Scholar]
  15. Hermeking H., Eick D. Mediation of c-Myc-induced apoptosis by p53. Science. 1994 Sep 30;265(5181):2091–2093. doi: 10.1126/science.8091232. [DOI] [PubMed] [Google Scholar]
  16. Korsmeyer S. J. Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood. 1992 Aug 15;80(4):879–886. [PubMed] [Google Scholar]
  17. Lapidot T., Pflumio F., Doedens M., Murdoch B., Williams D. E., Dick J. E. Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. Science. 1992 Feb 28;255(5048):1137–1141. doi: 10.1126/science.1372131. [DOI] [PubMed] [Google Scholar]
  18. Larochelle A., Vormoor J., Lapidot T., Sher G., Furukawa T., Li Q., Shultz L. D., Olivieri N. F., Stamatoyannopoulos G., Dick J. E. Engraftment of immune-deficient mice with primitive hematopoietic cells from beta-thalassemia and sickle cell anemia patients: implications for evaluating human gene therapy protocols. Hum Mol Genet. 1995 Feb;4(2):163–172. doi: 10.1093/hmg/4.2.163. [DOI] [PubMed] [Google Scholar]
  19. McCune J. M., Namikawa R., Kaneshima H., Shultz L. D., Lieberman M., Weissman I. L. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988 Sep 23;241(4873):1632–1639. doi: 10.1126/science.241.4873.1632. [DOI] [PubMed] [Google Scholar]
  20. McDonnell T. J., Troncoso P., Brisbay S. M., Logothetis C., Chung L. W., Hsieh J. T., Tu S. M., Campbell M. L. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res. 1992 Dec 15;52(24):6940–6944. [PubMed] [Google Scholar]
  21. Motoyama N., Wang F., Roth K. A., Sawa H., Nakayama K., Nakayama K., Negishi I., Senju S., Zhang Q., Fujii S. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science. 1995 Mar 10;267(5203):1506–1510. doi: 10.1126/science.7878471. [DOI] [PubMed] [Google Scholar]
  22. Nunez G., Seto M., Seremetis S., Ferrero D., Grignani F., Korsmeyer S. J., Dalla-Favera R. Growth- and tumor-promoting effects of deregulated BCL2 in human B-lymphoblastoid cells. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4589–4593. doi: 10.1073/pnas.86.12.4589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nuñez G., Clarke M. F. The Bcl-2 family of proteins: regulators of cell death and survival. Trends Cell Biol. 1994 Nov;4(11):399–403. doi: 10.1016/0962-8924(94)90053-1. [DOI] [PubMed] [Google Scholar]
  24. Ramqvist T., Magnusson K. P., Wang Y., Szekely L., Klein G., Wiman K. G. Wild-type p53 induces apoptosis in a Burkitt lymphoma (BL) line that carries mutant p53. Oncogene. 1993 Jun;8(6):1495–1500. [PubMed] [Google Scholar]
  25. Ryan J. J., Danish R., Gottlieb C. A., Clarke M. F. Cell cycle analysis of p53-induced cell death in murine erythroleukemia cells. Mol Cell Biol. 1993 Jan;13(1):711–719. doi: 10.1128/mcb.13.1.711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Salloum E., Reiss M., Cooper D. Detection and viability of tumor cells in peripheral blood stem cell and bone marrow collections from breast cancer patients. Blood. 1994 Apr 1;83(7):2007–2008. [PubMed] [Google Scholar]
  27. Schwartz R. M., Emerson S. G., Clarke M. F., Palsson B. O. In vitro myelopoiesis stimulated by rapid medium exchange and supplementation with hematopoietic growth factors. Blood. 1991 Dec 15;78(12):3155–3161. [PubMed] [Google Scholar]
  28. Shaw P., Bovey R., Tardy S., Sahli R., Sordat B., Costa J. Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4495–4499. doi: 10.1073/pnas.89.10.4495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Treleaven J. G., Gibson F. M., Ugelstad J., Rembaum A., Philip T., Caine G. D., Kemshead J. T. Removal of neuroblastoma cells from bone marrow with monoclonal antibodies conjugated to magnetic microspheres. Lancet. 1984 Jan 14;1(8368):70–73. doi: 10.1016/s0140-6736(84)90004-7. [DOI] [PubMed] [Google Scholar]
  30. Vaux D. L., Cory S., Adams J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988 Sep 29;335(6189):440–442. doi: 10.1038/335440a0. [DOI] [PubMed] [Google Scholar]
  31. Yang Y., Nunes F. A., Berencsi K., Furth E. E., Gönczöl E., Wilson J. M. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4407–4411. doi: 10.1073/pnas.91.10.4407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Yonish-Rouach E., Resnitzky D., Lotem J., Sachs L., Kimchi A., Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature. 1991 Jul 25;352(6333):345–347. doi: 10.1038/352345a0. [DOI] [PubMed] [Google Scholar]

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