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Characterization of the p53 Tumor Suppressor Pathway in Cell Lines of the National Cancer Institute Anticancer Drug Screen and Correlations with the Growth-Inhibitory Potency of 123 Anticancer Agents

Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892 [P. M. O., J. J., I. B., T. G. M., S. Fa., M. M., J. N. W., A. J. F., K. W. K.]; Developmental Therapeutics Program, National Cancer Institute, Frederick Cancer Research & Development Center, Frederick, Maryland 21702 [D. A. S., A. M., E. A. S.]; and Laboratory of Molecular Pharmacology, Fred Hutchinson Cancer Center, Seattle, Washington 98104 [S. Fr.]

In the present study, we report the characterization of the p53 tumor suppressor pathway in the 60 cell lines of the National Cancer Institute (NCI) anticancer drug screen, as well as correlations between the integrity of this pathway and the growth-inhibitory potency of 123 anticancer agents in this screen. Assessment of p53 status in these lines was achieved through complete p53 cDNA sequencing, measurement of basal p53 protein levels and functional assessment of (a) transcriptional activity of p53 cDNA from each line in a yeast assay, (b) -ray-induced G₁ phase cell cycle arrest, and (c) -ray-induced expression of CIP1/WAF1, GADD45, and MDM2 mRNA. Our investigations revealed that p53 gene mutations were common in the NCI cell screen lines: 39 of 58 cell lines analyzed contained a mutant p53 sequence. cDNA derived from almost all of the mutant p53 cell lines failed to transcriptionally activate a reporter gene in yeast, and the majority of mutant p53 lines studied expressed elevated basal levels of the mutant p53 protein. In contrast to most of the wild-type p53-containing lines, cells containing mutant p53 sequence were also deficient in -ray induction of CIP1/WAF1, GADD45, and MDM2 mRNA and the ability to arrest in G₁ following -irradiation. Taken together, these assessments provided indications of the integrity of the p53 pathway in the 60 cell lines of the NCI cell screen. These individual p53 assessments were subsequently used to probe a database of growth-inhibitory potency for 123 "standard agents," which included the majority of clinically approved anticancer drugs. These 123 agents have been tested against these lines on multiple occasions, and a proposed mechanism of drug action had previously been assigned to each agent. Our analysis revealed that cells with mutant p53 sequence tended to exhibit less growth inhibition in this screen than the wild-type p53 cell lines when treated with the majority of clinically used anticancer agents: including DNA cross-linking agents, antimetabolites, and topoisomerase I and II inhibitors. Similar correlations were uncovered when we probed this database using most of the other indices of p53 status we assessed in the lines. Interestingly, a class of agents that differed in this respect was the antimitotic agents. Growth-inhibitory activity of these agents tended, in this assay, to be independent of p53 status. Our characterization of the p53 pathway in the NCI cell screen lines should prove useful to researchers investigating fundamental aspects of p53 biology and pharmacology. This information also allows for the large-scale analysis of the more than 60,000 compounds tested against these lines for novel agents that might exploit defective p53 function as a means of preferential toxicity.

¹ To whom requests for reprints should be addressed, at Laboratory of Molecular Pharmacology, Division of Basic Science, Building 37, Room 5C25, National Cancer Institute, NIH, Bethesda, MD 20892. Phone: (301) 435-2848; Fax: (301) 402-0752; E-mail: oconnorp@dc37a.nci.nih.gov.

Received 4/25/97. Accepted 7/25/97.

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				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. Russo, D. Arzani, S. Trombino, and C. Falugi c-myc Down-Regulation Induces Apoptosis in Human Cancer Cell Lines Exposed to RPR-115135 (C31H29NO4), a Non-Peptidomimetic Farnesyltransferase Inhibitor J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 37 - 47. [Abstract] [Full Text] [PDF]

				S. Yang, J. Chen, Z. Guo, X.-M. Xu, L. Wang, X.-F. Pei, J. Yang, C. B. Underhill, and L. Zhang Triptolide Inhibits the Growth and Metastasis of Solid Tumors Mol. Cancer Ther., January 1, 2003; 2(1): 65 - 72. [Abstract] [Full Text] [PDF]

				S. Bolshakov, C. M. Walker, S. S. Strom, M. S. Selvan, G. L. Clayman, A. El-Naggar, S. M. Lippman, M. L. Kripke, and H. N. Ananthaswamy p53 Mutations in Human Aggressive and Nonaggressive Basal and Squamous Cell Carcinomas Clin. Cancer Res., January 1, 2003; 9(1): 228 - 234. [Abstract] [Full Text] [PDF]

				D. Pati, N. Zhang, and S. E. Plon Linking Sister Chromatid Cohesion and Apoptosis: Role of Rad21 Mol. Cell. Biol., December 1, 2002; 22(23): 8267 - 8277. [Abstract] [Full Text] [PDF]

				V. J.N. Bykov, N. Issaeva, G. Selivanova, and K. G. Wiman Mutant p53-dependent growth suppression distinguishes PRIMA-1 from known anticancer drugs: a statistical analysis of information in the National Cancer Institute database Carcinogenesis, December 1, 2002; 23(12): 2011 - 2018. [Abstract] [Full Text] [PDF]

				S. T. Nawrocki, C. J. Bruns, M. T. Harbison, R. J. Bold, B. S. Gotsch, J. L. Abbruzzese, P. Elliott, J. Adams, and D. J. McConkey Effects of the Proteasome Inhibitor PS-341 on Apoptosis and Angiogenesis in Orthotopic Human Pancreatic Tumor Xenografts Mol. Cancer Ther., December 1, 2002; 1(14): 1243 - 1253. [Abstract] [Full Text] [PDF]

				H. Zhang, X. Shi, Q.-J. Zhang, M. Hampong, H. Paddon, D. Wahyuningsih, and S. Pelech Nocodazole-induced p53-dependent c-Jun N-terminal Kinase Activation Reduces Apoptosis in Human Colon Carcinoma HCT116 Cells J. Biol. Chem., November 8, 2002; 277(46): 43648 - 43658. [Abstract] [Full Text] [PDF]

				V. W. van Beusechem, P. B. van den Doel, J. Grill, H. M. Pinedo, and W. R. Gerritsen Conditionally Replicative Adenovirus Expressing p53 Exhibits Enhanced Oncolytic Potency Cancer Res., November 1, 2002; 62(21): 6165 - 6171. [Abstract] [Full Text] [PDF]

				D.-G. Kim, K.-R. You, M.-J. Liu, Y.-K. Choi, and Y.-S. Won GADD153-mediated Anticancer Effects of N-(4-Hydroxyphenyl)retinamide on Human Hepatoma Cells J. Biol. Chem., October 4, 2002; 277(41): 38930 - 38938. [Abstract] [Full Text] [PDF]

				J. Wen, K.-R. You, S.-Y. Lee, C.-H. Song, and D.-G. Kim Oxidative Stress-mediated Apoptosis. THE ANTICANCER EFFECT OF THE SESQUITERPENE LACTONE PARTHENOLIDE J. Biol. Chem., October 4, 2002; 277(41): 38954 - 38964. [Abstract] [Full Text] [PDF]

				J. L. Bronder and R. G. Moran Antifolates Targeting Purine Synthesis Allow Entry of Tumor Cells into S Phase Regardless of p53 Function Cancer Res., September 15, 2002; 62(18): 5236 - 5241. [Abstract] [Full Text] [PDF]

				J. E. Mullally and F. A. Fitzpatrick Pharmacophore Model for Novel Inhibitors of Ubiquitin Isopeptidases That Induce p53-Independent Cell Death Mol. Pharmacol., August 1, 2002; 62(2): 351 - 358. [Abstract] [Full Text] [PDF]

				C. Pipaon, P. Gutierrez, J. C. Montero, M. Lorenzo, A. Eguiraun, J. A. De la Fuente, A. Pandiella, J. Leon, and J. M. Ortiz Mitogen-activated Protein Kinase Routes as Targets in the Action of Diaza-anthracene Compounds with a Potent Growth-inhibitory Effect on Cancer Cells Mol. Cancer Ther., August 1, 2002; 1(10): 811 - 819. [Abstract] [Full Text] [PDF]

				Y. Imai, M. Nakane, K. Kage, S. Tsukahara, E. Ishikawa, T. Tsuruo, Y. Miki, and Y. Sugimoto C421A Polymorphism in the Human Breast Cancer Resistance Protein Gene Is Associated with Low Expression of Q141K Protein and Low-Level Drug Resistance Mol. Cancer Ther., June 1, 2002; 1(8): 611 - 616. [Abstract] [Full Text] [PDF]

				D. DeFeo-Jones, S. F. Brady, D.-M. Feng, B. K. Wong, T. Bolyar, K. Haskell, D. M. Kiefer, K. Leander, E. McAvoy, P. Lumma, et al. A Prostate-specific Antigen (PSA)-activated Vinblastine Prodrug Selectively Kills PSA-secreting Cells in Vivo Mol. Cancer Ther., May 1, 2002; 1(7): 451 - 459. [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]

				Y. Zhou, F. G. Gwadry, W. C. Reinhold, L. D. Miller, L. H. Smith, U. Scherf, E. T. Liu, K. W. Kohn, Y. Pommier, and J. N. Weinstein Transcriptional Regulation of Mitotic Genes by Camptothecin-induced DNA Damage: Microarray Analysis of Dose- and Time-dependent Effects Cancer Res., March 1, 2002; 62(6): 1688 - 1695. [Abstract] [Full Text] [PDF]

				P. B. Cassidy, P. J. Moos, R. C. Kelly, and F. A. Fitzpatrick Cyclooxygenase-2 Induction by Paclitaxel, Docetaxel, and Taxane Analogues in Human Monocytes and Murine Macrophages: Structure-Activity Relationships and Their Implications Clin. Cancer Res., March 1, 2002; 8(3): 846 - 855. [Abstract] [Full Text] [PDF]

				K. Szepeshazi, A. V. Schally, G. Halmos, P. Armatis, F. Hebert, B. Sun, A. Feil, H. Kiaris, and A. Nagy Targeted Cytotoxic Somatostatin Analogue AN-238 Inhibits Somatostatin Receptor-positive Experimental Colon Cancers Independently of Their p53 Status Cancer Res., February 1, 2002; 62(3): 781 - 788. [Abstract] [Full Text] [PDF]

				C. Huisman, C. G. Ferreira, L. E. Broker, J. A. Rodriguez, E. F. Smit, P. E. Postmus, F. A. E. Kruyt, and G. Giaccone Paclitaxel Triggers Cell Death Primarily via Caspase-independent Routes in the Non-Small Cell Lung Cancer Cell Line NCI-H460 Clin. Cancer Res., February 1, 2002; 8(2): 596 - 606. [Abstract] [Full Text] [PDF]

				P. Russo, C. Ottoboni, D. Malacarne, A. Crippa, J.-F. Riou, and P. M. O'Connor Nonpeptidomimetic Farnesyltransferase Inhibitor RPR-115135 Increases Cytotoxicity of 5-Fluorouracil: Role of p53 J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 220 - 226. [Abstract] [Full Text] [PDF]

				K. W. Crawford and W. D. Bowen Sigma-2 Receptor Agonists Activate a Novel Apoptotic Pathway and Potentiate Antineoplastic Drugs in Breast Tumor Cell Lines Cancer Res., January 1, 2002; 62(1): 313 - 322. [Abstract] [Full Text] [PDF]

				K. B. Kim, R. Lotan, P. Yue, M. B. Sporn, N. Suh, G. W. Gribble, T. Honda, G. S. Wu, W. K. Hong, and S.-Y. Sun Identification of a Novel Synthetic Triterpenoid, Methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate, That Potently Induces Caspase-mediated Apoptosis in Human Lung Cancer Cells Mol. Cancer Ther., January 1, 2002; 1(3): 177 - 184. [Abstract] [Full Text] [PDF]

				P. Karran Mechanisms of tolerance to DNA damaging therapeutic drugs Carcinogenesis, December 1, 2001; 22(12): 1931 - 1937. [Abstract] [Full Text] [PDF]

				D. L. Kramer, B.-D. Chang, Y. Chen, P. Diegelman, K. Alm, A. R. Black, I. B. Roninson, and C. W. Porter Polyamine Depletion in Human Melanoma Cells Leads to G1 Arrest Associated with Induction of p21WAF1/CIP1/SDI1, Changes in the Expression of p21-regulated Genes, and a Senescence-like Phenotype Cancer Res., November 1, 2001; 61(21): 7754 - 7762. [Abstract] [Full Text] [PDF]

				V. Smith, F. Raynaud, P. Workman, and L. R. Kelland Characterization of a Human Colorectal Carcinoma Cell Line with Acquired Resistance to Flavopiridol Mol. Pharmacol., November 1, 2001; 60(5): 885 - 893. [Abstract] [Full Text] [PDF]

				H. Wang, L. Nan, D. Yu, S. Agrawal, and R. Zhang Antisense Anti-MDM2 Oligonucleotides As a Novel Therapeutic Approach to Human Breast Cancer: In Vitro and in Vivo Activities and Mechanisms Clin. Cancer Res., November 1, 2001; 7(11): 3613 - 3624. [Abstract] [Full Text] [PDF]

				R. D. Abeysinghe, B. T. Greene, R. Haynes, M. C. Willingham, J. Turner, R. P. Planalp, M.W. Brechbiel, F. M. Torti, and S. V. Torti p53-independent apoptosis mediated by tachpyridine, an anti-cancer iron chelator Carcinogenesis, October 1, 2001; 22(10): 1607 - 1614. [Abstract] [Full Text] [PDF]