Clinical Cancer Research, Vol 2, Issue 10 1649-1657, Copyright © 1996 by American Association for Cancer Research

ARTICLES

Wild-type p53 protein potentiates cytotoxicity of therapeutic agents in human colon cancer cells

B Yang, JR Eshleman, NA Berger and SD Markowitz
Department of Molecular Biology, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.

Wild-type p53 is induced by DNA damage. In different cell types, this induction is suggested either to facilitate DNA repair by inducing a cell cycle pause or to potentiate cell death via apoptosis. Wild-type p53 in different cell types has similarly been associated with either enhancement of or increased resistance to the cytotoxicity of many cancer therapeutic agents. We have constructed a colorectal cancer cell line bearing, in addition to endogenous mutant p53 alleles, an exogenous wild-type p53 allele that is under the regulatable control of the lac repressor. Induction of wild-type p53 by isopropyl-beta-thiogalactopyranoside in these cells induces a reversible growth arrest but does not induce cell death. However, we find that the induction of wild-type p53 powerfully potentiates the cytotoxicity of both irradiation and 5-fluorouracil, two agents that are used clinically in the treatment of colorectal cancer. We also find that induction of wild-type p53 potentiates the cytotoxicity of topotecan, a member of the camptothecin family of drugs that also has clinical activity against colon cancer. These findings suggest that the common loss of wild-type p53 in many colorectal cancers may play a role in the clinical resistance of these tumors to anticancer agents. Although some cancer cells may not be directly killed by p53 gene therapy, our findings suggest that genetic alteration of some cancers to induce wild-type p53 may increase their sensitivity to cytotoxic gene therapy.

This article has been cited by other articles:

				T. Hata, H. Yamamoto, C. Y. Ngan, M. Koi, A. Takagi, B. Damdinsuren, M. Yasui, Y. Fujie, T. Matsuzaki, H. Hemmi, et al. Role of p21waf1/cip1 in effects of oxaliplatin in colorectal cancer cells Mol. Cancer Ther., October 1, 2005; 4(10): 1585 - 1594. [Abstract] [Full Text] [PDF]

				J. Boyer, E. G. McLean, S. Aroori, P. Wilson, A. McCulla, P. D. Carey, D. B. Longley, and P. G. Johnston Characterization of p53 Wild-Type and Null Isogenic Colorectal Cancer Cell Lines Resistant to 5-Fluorouracil, Oxaliplatin, and Irinotecan Clin. Cancer Res., March 15, 2004; 10(6): 2158 - 2167. [Abstract] [Full Text] [PDF]

				J. M. Mariadason, D. Arango, Q. Shi, A. J. Wilson, G. A. Corner, C. Nicholas, M. J. Aranes, M. Lesser, E. L. Schwartz, and L. H. Augenlicht Gene Expression Profiling-Based Prediction of Response of Colon Carcinoma Cells to 5-Fluorouracil and Camptothecin Cancer Res., December 15, 2003; 63(24): 8791 - 8812. [Abstract] [Full Text] [PDF]

				C. J. Allegra, S. Paik, L. H. Colangelo, A. L. Parr, I. Kirsch, G. Kim, P. Klein, P. G. Johnston, N. Wolmark, and H. S. Wieand Prognostic Value of Thymidylate Synthase, Ki-67, and p53 in Patients With Dukes' B and C Colon Cancer: A National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study J. Clin. Oncol., January 15, 2003; 21(2): 241 - 250. [Abstract] [Full Text] [PDF]

				P. P. McKenzie, C. R. McPake, A. A. Ashford, E. F. Vanin, and L. C. Harris MDM2 Does Not Influence p53-mediated Sensitivity to DNA-damaging Drugs Mol. Cancer Ther., October 1, 2002; 1(12): 1097 - 1104. [Abstract] [Full Text] [PDF]

				C. J. Allegra, A. L. Parr, L. E. Wold, M. R. Mahoney, D. J. Sargent, P. Johnston, P. Klein, K. Behan, M. J. O'Connell, R. Levitt, et al. Investigation of the Prognostic and Predictive Value of Thymidylate Synthase, p53, and Ki-67 in Patients With Locally Advanced Colon Cancer J. Clin. Oncol., April 1, 2002; 20(7): 1735 - 1743. [Abstract] [Full Text] [PDF]

				R. Garcia-Carbonero and J. G. Supko Current Perspectives on the Clinical Experience, Pharmacology, and Continued Development of the Camptothecins Clin. Cancer Res., March 1, 2002; 8(3): 641 - 661. [Abstract] [Full Text] [PDF]

				D. Arango, G. A. Corner, S. Wadler, P. J. Catalano, and L. H. Augenlicht c-myc/p53 Interaction Determines Sensitivity of Human Colon Carcinoma Cells to 5-Fluorouracil in Vitro and in Vivo Cancer Res., June 1, 2001; 61(12): 4910 - 4915. [Abstract] [Full Text] [PDF]

				N. Shinoura, Y. Muramatsu, M. Nishimura, Y. Yoshida, A. Saito, T. Yokoyama, T. Furukawa, A. Horii, M. Hashimoto, A. Asai, et al. Adenovirus-mediated Transfer of p33ING1 with p53 Drastically Augments Apoptosis in Gliomas Cancer Res., November 1, 1999; 59(21): 5521 - 5528. [Abstract] [Full Text] [PDF]

				E. Perz and J. G. Kuhn Review : p53 in the pathogenesis, diagnosis, and treatment of cancer Journal of Oncology Pharmacy Practice, June 1, 1998; 4(2): 75 - 102. [Abstract] [PDF]