This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Achenbach, T. V. Articles by Slater, E. P. Search for Related Content PubMed PubMed Citation Articles by Achenbach, T. V. Articles by Slater, E. P.

Synergistic Antitumor Effect of Chemotherapy and Antisense-mediated Ablation of the Cell Cycle Inhibitor p27^KIP-11

Institute of Molecular Biology and Tumor Research (IMT), Philipps University, D-35033 Marburg, Germany

The fraction of noncycling cells found in most tumors represents a major obstacle for conventional chemotherapy. Here, we show that the cyclin-dependent kinase inhibitor p27^KIP-1 accumulates to high levels in human tumors grown in immunodeficient mice. We have developed an antisense phosphorothioate oligodeoxynucleotide (ODN) that efficiently inhibits the expression of p27^KIP-1 both in vitro and in vivo. Treatment of cultured tumor cells with this ODN sensitized the cells to all chemotherapeutic drugs tested, including the new kinase inhibitor flavopiridol. Furthermore, striking synergistic effects of the p27^KIP-1 ODN and flavopiridol were observed in vivo with respect to both the induction of apoptotic cell death and the inhibition of tumor growth. Importantly, p27^KIP-1 ODN treatment alone did not provoke any detectable tumor enhancement. A mechanistic explanation for these findings might be derived from the observation that p27 ODN treatment of cultured tumor cells led to a clear increase in the fraction of S-G₂ cells in the absence of an efficient progression into M phase. These findings may have direct relevance to the development of new approaches for the treatment of human cancer.

This article has been cited by other articles:

				M. Filipits, R. Pirker, A. Dunant, S. Lantuejoul, K. Schmid, A. Huynh, V. Haddad, F. Andre, R. Stahel, J.-P. Pignon, et al. Cell Cycle Regulators and Outcome of Adjuvant Cisplatin-Based Chemotherapy in Completely Resected Non-Small-Cell Lung Cancer: The International Adjuvant Lung Cancer Trial Biologic Program J. Clin. Oncol., July 1, 2007; 25(19): 2735 - 2740. [Abstract] [Full Text] [PDF]

				H. G. Moore, J. Shia, D. S. Klimstra, L. Ruo, M. Mazumdar, G. K. Schwartz, B. D. Minsky, L. Saltz, and J. G. Guillem Expression of p27 in Residual Rectal Cancer after Preoperative Chemoradiation Predicts Long-term Outcome Ann. Surg. Oncol., November 1, 2004; 11(11): 955 - 961. [Abstract] [Full Text] [PDF]

				T. Ishii, M. Fujishiro, M. Masuda, Y. Goshima, H. Kitamura, S. Teramoto, and T. Matsuse Effects of p27Kip1 on cell cycle status and viability in A549 lung adenocarcinoma cells Eur. Respir. J., May 1, 2004; 23(5): 665 - 670. [Abstract] [Full Text] [PDF]

				C. B. Matranga and G. I. Shapiro Selective Sensitization of Transformed Cells to Flavopiridol-induced Apoptosis following Recruitment to S-Phase Cancer Res., March 1, 2002; 62(6): 1707 - 1717. [Abstract] [Full Text] [PDF]