Abstract
Radiation and traditional chemotherapy kill both normal and tumor cells owing to lack of target selectivity. In this chapter, we review methods for the use of antisense oligodeoxynucleotides (AS-DONs) directed against gene products overexpressed in tumor cells in synergy with other anticancer agents. In contrast to the low basal levels of the mitogen-dependent cyclin D1 and of the DNA-damage-inducible p53 tumor suppressor protein, tumors with greater genetic instability and poor therapeutic response show a mutant-stabilized p53 protein, a mitogen-independent constitutive cyclin D1, and overexpression of antiapoptotic genes such as bcl-2 and bcl-xL. Since overexpression of any one of these gene products decreases apoptosis in malignant cells, we propose the use of subtoxic antisense technology specifically directed against some of these tumor-associated targets prior to treatment with sublethal chemotherapy as a strategy to diminish damage to normal cells and the emergence of cancer cells resistant to conventional therapy. AS-ODN technology capable of antagonizing gene sequences preferentially expressed in tumors combined with standard anticancer therapy offers an alternative approach to improve target selectivity, diminish anticancer toxicity, and lower drug resistance.
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References
Rieber, M. and Strasberg-Rieber, M. (1999) Tumor suppression without differentiation or apoptosis by antisense cyclin D1 gene transfer in K1735 melanoma involves induction of p53,p21WAF1 and superoxide dismutases. Cell Death Differ. 6, 1209ā1215.
Steeg, P. and Zhou, Q. (1998) Cyclins and breast cancer. Breast Cancer Res. Treat. 52, 17ā28.
Hall, M. and Peters, G. (1996) Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv. Cancer Res. 68, 67ā108.
Sigal, A. and Rotter, V. (2000) Oncogenic mutations of the p53 tumor suppressor, the demons of the guardian of the genome. Cancer Res. 60, 6788ā6793.
Esteve, A., Lehman, T., Jiang, W., et al. (1993) Correlation of p53 mutation with epidermal growth factor receptor overexpression and mdm2 amplification in human esophageal carcinoma. Mol. Carcinog. 8, 306ā311.
Olie R. A., Hafner, C., Kuttel, R., et al. (2002) Bcl-2 and bcl-xL antisense oligonucleotides induce apoptosis in melanoma cells of different clinical stages. J. Invest. Dermatol. 118, 505ā512.
Mineta, H., Borg, A., Dictor, M., Wahlbert, P., and Wennerberg, J. (1997) Correlation between p53 mutation and cyclin D1 amplification in head and neck squamous cell carcinoma. Oral Oncol. 33, 42ā46.
Mueller, A., Odze, R., Jenkins, T. D., et al. (1997) A transgenic mouse model with cyclin D1 overexpression results in cell cycle, epidermal growth factor receptor, and p53 abnormalities. Cancer Res. 57, 5542ā5549.
Lin, H. M., Lee, Y. J., Li, G., Pestell, R. G., and Kim, H. R. (2001) Bcl-2 induces cyclin D1 promoter activity in human breast epithelial cells independent of cell anchorage. Cell Death Differ. 8, 44ā50.
Smith, L., Andersen, K. B., Hovgaard, L., and Jaroszewski, J. W. (2000) Rational selection of antisense oligonucleotide sequences. Eur. J. Pharm. Sci. 11, 191ā198.
Olie, R. A., Hall, J., Natt, F., Stahel, R. A., and Zangemeister-Wittke, U. (2002) Analysis of ribosyl-modified, mixed backbone analogs of a bcl-2/bcl-xL antisense oligonucleotide. Biochim. Biophys. Acta 1576, 101ā109.
Strasberg-Rieber, M., Zangemeister-Wittke, U., and Rieber, M. (2001) p53-independent induction of apoptosis in human melanoma cells by a bcl2/bcl-xL bispecific antisense oligonucleotide. Clinical Cancer Res. 7, 1446ā1451.
OāBrien, J., Wilson, I., Orton, T., and Pognan, F. (2000) Investigation of the Alamar Blue (resazurin) fluorescent dyefor the assesment of mammalian cell cytotoxicity. Eur. J. Biochem. 267, 5421ā5426.
Barton, C. M. and Lemoine, N. R. (1995) Antisense oligonucleotides directed against p53 have antiproliferative effects unrelated to effects on p53 expression. British J. Cancer 71, 429ā437.
Vilenchik, M., Raffo, A. J., Benimetskaya, L., Shames, D., and Stein, C. A. (2002) Antisense RNA down-regulation of bcl-xL expression in prostate cancer cells leads to diminished rates of cellular proliferation and resistance to cytotoxic therapeutic agents. Cancer Res. 62, 2175ā2183.
Milas, L., Akimoto, T., Hunter, N. R., et al. (2002) Relationship between cyclin D1 expression and poor radioresponse of murine carcinomas. Int. J. Radiat. Oncol. Biol. Phys. 52, 514ā521
Curtis, R. E., Freedman, D. M., Sherman, M. E., Fraumeni, J. F., Jr. (2004) Risk of malignant mixed mullerian tumors after tamoxifen therapy for breast cancer. J. Natl. Cancer Inst. 96(1), 70ā74.
Zhang, G.-J., Kimijima, I., Onda, M., Sato, H., Watanabe, T., Tsuchiya, A., Abe, R., and Takenoshita, S. (1999) Tamoxifen-induced apoptosis in breast cancer cells relates to down-regulation of bcl-2 but not bax and bcl-xl, without alteration of p53 protein levels. Clin. Cancer Res. 5, 2971ā2977.
Simoes-Wust, A. P., Olie, R. A., Gautschi, O., et al. (2000) Bcl-xl antisense treatment induces apoptosis in breast carcinoma cells. Int. J. Cancer. 87, 582ā590.
Heere-Ress, E., Thallinger, C., Lucas, T., et al. (2002) Bcl-X(L) is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy. Int. J. Cancer 99, 29ā34.
Wacheck, V., Heere-Ress, E., Halaschek-Wiener, J., et al. (2001) Bcl-2 antisense oligonucleotides chemosensitize human gastric cancer in a SCID mouse xenotransplantation model. J. Mol. Med. 79, 587ā93.
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Rieber, M., Strasberg-Rieber, M. (2005). Induction of Tumor Cell Apoptosis and Chemosensitization by Antisense Strategies. In: Phillips, M.I. (eds) Antisense Therapeutics. Methods in Molecular Medicineā¢, vol 106. Humana Press. https://doi.org/10.1385/1-59259-854-4:205
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DOI: https://doi.org/10.1385/1-59259-854-4:205
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