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Science 17 January 1997:
Vol. 275. no. 5298, pp. 343 - 349
DOI: 10.1126/science.275.5298.343
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Articles

An Information-Intensive Approach to the Molecular Pharmacology of Cancer

John N. Weinstein, * Timothy G. Myers, Patrick M. O'Connor, Stephen H. Friend, Albert J. Fornace Jr., Kurt W. Kohn, Tito Fojo, Susan E. Bates, Lawrence V. Rubinstein, N. Leigh Anderson, John K. Buolamwini, dagger William W. van Osdol, ddagger Anne P. Monks, Dominic A. Scudiero, Edward A. Sausville, Daniel W. Zaharevitz, Barry Bunow, Vellarkad N. Viswanadhan, § George S. Johnson, Robert E. Wittes, Kenneth D. Paull

Since 1990, the National Cancer Institute (NCI) has screened more than 60,000 compounds against a panel of 60 human cancer cell lines. The 50-percent growth-inhibitory concentration (GI50) for any single cell line is simply an index of cytotoxicity or cytostasis, but the patterns of 60 such GI50 values encode unexpectedly rich, detailed information on mechanisms of drug action and drug resistance. Each compound's pattern is like a fingerprint, essentially unique among the many billions of distinguishable possibilities. These activity patterns are being used in conjunction with molecular structural features of the tested agents to explore the NCI's database of more than 460,000 compounds, and they are providing insight into potential target molecules and modulators of activity in the 60 cell lines. For example, the information is being used to search for candidate anticancer drugs that are not dependent on intact p53 suppressor gene function for their activity. It remains to be seen how effective this information-intensive strategy will be at generating new clinically active agents.

J. N. Weinstein, T. G. Myers, P. M. O'Connor, A. J. Fornace Jr., K. W. Kohn, J. K. Buolamwini, W. W. van Osdol, and V. N. Viswanadhan are at the Laboratory of Molecular Pharmacology (LMP), Division of Basic Science, National Cancer Institute (NCI), National Institutes of Health (NIH), Building 37, Room 5C-25, 9000 Rockville Pike, Bethesda, MD 20892, USA. S. H. Friend is at the Fred Hutchinson Cancer Research Center-NCI, Seattle, WA 98105, USA. T. Fojo and S. E. Bates are in the Medicine Branch, Division of Clinical Science, NCI, NIH, Bethesda, MD 20892, USA. L. V. Rubinstein is in the Biometric Research Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, Diagnosis, and Centers (DCTDC), NCI, NIH, Bethesda, MD 20892, USA. N. L. Anderson is with Large Scale Biology, Rockville, MD 20850, USA. A. P. Monks and D. A. Scudiero are at the SAIC-NCI-Frederick Cancer Research and Development Center (FCRDC), Frederick, MD 21701, USA. E. A. Sausville is in the Developmental Therapeutics Program (DTP), DCTDC, NCI, NIH, Bethesda, MD 20892, USA. D. W. Zaharevitz and K. D. Paull are in the Information Technology Branch, DTP, DCTDC, NCI, NIH, Bethesda, MD 20892, USA. G. S. Johnson is in the Grants and Contracts Operations Branch, DTP, DCTDC, NCI, NIH, Bethesda, MD 20892, USA. R. E. Wittes is in the Office of the Director, DCTDC, NCI, NIH, Bethesda, MD 20892, USA.
*   To whom correspondence should be addressed. E-mail: weinstein{at}dtpax2.ncifcrf.gov

dagger    Present address: University of Mississippi School of Pharmacy, University of Mississippi, MS 38677, USA.

ddagger    Present address: Alza, 1454 Page Mill Road, Palo Alto, CA 94304, USA.

§   Present address: Gensia, 9360 Towne Center Drive, San Diego, CA 92121, USA.

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Human and Experimental Toxicology 21, 115-122
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Transcriptional Regulation of Mitotic Genes by Camptothecin-induced DNA Damage: Microarray Analysis of Dose- and Time-dependent Effects.
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 (2002)
Cancer Res. 62, 1688-1695
   Abstract »    Full Text »    PDF »
Establishing Connections between Microarray Expression Data and Chemotherapeutic Cancer Pharmacology.
A. Wallqvist, A. A. Rabow, R. H. Shoemaker, E. A. Sausville, and D. G. Covell (2002)
Mol. Cancer Ther. 1, 311-320
   Abstract »    Full Text »    PDF »
Intratumoral 5-Fluorouracil Produced by Cytosine Deaminase/5-Fluorocytosine Gene Therapy Is Effective for Experimental Human Glioblastomas.
C. R. Miller, C. R. Williams, D. J. Buchsbaum, and G. Y. Gillespie (2002)
Cancer Res. 62, 773-780
   Abstract »    Full Text »    PDF »
Evolution of Anticancer Drug Discovery and the Role of Cell-Based Screening.
F. M. Balis (2002)
J Natl Cancer Inst 94, 78-79
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CELL CYCLE DYSREGULATION IN ORAL CANCER.
R. Todd, P.W. Hinds, K. Munger, A.K. Rustgi, O.G. Opitz, Y. Suliman, and D.T. Wong (2002)
Critical Reviews in Oral Biology & Medicine 13, 51-61
   Abstract »    Full Text »    PDF »
Correlation of p53 Mutations with Resistance to Platinum-based Chemotherapy and Shortened Survival in Ovarian Cancer.
A. Reles, W. H. Wen, A. Schmider, C. Gee, I. B. Runnebaum, U. Kilian, L. A. Jones, A. El-Naggar, C. Minguillon, I. Schonborn, et al. (2001)
Clin. Cancer Res. 7, 2984-2997
   Abstract »    Full Text »    PDF »
Chemosensitivity prediction by transcriptional profiling.
J. E. Staunton, D. K. Slonim, H. A. Coller, P. Tamayo, M. J. Angelo, J. Park, U. Scherf, J. K. Lee, W. O. Reinhold, J. N. Weinstein, et al. (2001)
PNAS 98, 10787-10792
   Abstract »    Full Text »    PDF »
Selective Activation of Apoptosis Program by S-p-bromobenzylglutathione Cyclopentyl Diester in Glyoxalase I-overexpressing Human Lung Cancer Cells.
H. Sakamoto, T. Mashima, S. Sato, Y. Hashimoto, T. Yamori, and T. Tsuruo (2001)
Clin. Cancer Res. 7, 2513-2518
   Abstract »    Full Text »    PDF »
The Case for a New National Program for the Development of Cancer Therapeutics.
P. S. Schein (2001)
J. Clin. Oncol. 19, 3142-3153
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Thymidine Kinase, Thymidylate Synthase, and Dihydropyrimidine Dehydrogenase Profiles of Cell Lines of the National Cancer Institute's Anticancer Drug Screen.
J. L. Grem, K. D. Danenberg, K. Behan, A. Parr, L. Young, P. V. Danenberg, D. Nguyen, J. Drake, A. Monks, and C. J. Allegra (2001)
Clin. Cancer Res. 7, 999-1009
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P450 Enzyme Expression Patterns in the NCI Human Tumor Cell Line Panel.
L. J. Yu, J. Matias, D. A. Scudiero, K. M. Hite, A. Monks, E. A. Sausville, and D. J. Waxman (2001)
Drug Metab. Dispos. 29, 304-312
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Establishment of a Chemical Synthetic Lethality Screen in Cultured Human Cells.
A. Simons, N. Dafni, I. Dotan, Y. Oron, and D. Canaani (2001)
Genome Res. 11, 266-273
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Toxicogenomics-Based Discrimination of Toxic Mechanism in HepG2 Human Hepatoma Cells.
M. E. Burczynski, M. McMillian, J. Ciervo, L. Li, J. B. Parker, R. T. Dunn II, S. Hicken, S. Farr, and M. D. Johnson (2000)
Toxicol. Sci. 58, 399-415
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Chemotherapy Triggers Apoptosis in a Caspase-8-dependent and Mitochondria-controlled Manner in the Non-Small Cell Lung Cancer Cell Line NCI-H460.
C. G. Ferreira, S. W. Span, G. J. Peters, F. A. E. Kruyt, and G. Giaccone (2000)
Cancer Res. 60, 7133-7141
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Pharmacogenomics -- Teaching Old Drugs New Tricks.
J. N. Weinstein (2000)
N. Engl. J. Med. 343, 1408-1409
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An Informatics Approach Identifying Markers of Chemosensitivity in Human Cancer Cell Lines.
S. A. Amundson, T. G. Myers, D. Scudiero, S. Kitada, J. C. Reed, and A. J. Fornace Jr. (2000)
Cancer Res. 60, 6101-6110
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Predicting Tumor Responses to Mitomycin C on the Basis of DT-Diaphorase Activity or Drug Metabolism by Tumor Homogenates: Implications for Enzyme-directed Bioreductive Drug Development.
R. M. Phillips, A. M. Burger, P. M. Loadman, C. M. Jarrett, D. J. Swaine, and H.-H. Fiebig (2000)
Cancer Res. 60, 6384-6390
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Discovering functional relationships between RNA expression and chemotherapeutic susceptibility using relevance networks.
A. J. Butte, P. Tamayo, D. Slonim, T. R. Golub, and I. S. Kohane (2000)
PNAS
   Abstract »    Full Text »
Expression of breast cancer resistance protein in blast cells from patients with acute leukemia.
D. D. Ross, J. E. Karp, T. T. Chen, and L. A. Doyle (2000)
Blood 96, 365-368
   Abstract »    Full Text »    PDF »
Systematic Management and Analysis of Yeast Gene Expression Data.
J. Aach, W. Rindone, and G. M. Church (2000)
Genome Res. 10, 431-445
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Epstein-Barr Virus Suppresses a G2/M Checkpoint Activated by Genotoxins.
M. Wade and M. J. Allday (2000)
Mol. Cell. Biol. 20, 1344-1360
   Abstract »    Full Text »    PDF »
Activity of Docetaxel in Platinum-Treated Non-Small-Cell Lung Cancer: Results of a Phase II Multicenter Trial.
D. R. Gandara, E. Vokes, M. Green, P. Bonomi, R. Devore, R. Comis, D. Carbone, D. Karp, and C. Belani (2000)
J. Clin. Oncol. 18, 131
   Abstract »    Full Text »    PDF »
Antifungal Activities of Antineoplastic Agents: Saccharomyces cerevisiae as a Model System To Study Drug Action.
M. E. Cardenas, M. C. Cruz, M. Del Poeta, N. Chung, J. R. Perfect, and J. Heitman (1999)
Clin. Microbiol. Rev. 12, 583-611
   Abstract »    Full Text »    PDF »
Large-Scale Statistical Analyses of Rice ESTs Reveal Correlated Patterns of Gene Expression.
R. M. Ewing, A. B. Kahla, O. Poirot, F. Lopez, S. Audic, and J.-M. Claverie (1999)
Genome Res. 9, 950-959
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Correction for vol. 95, p. 14863.
(1999)
PNAS 96, 10943
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Computational methods for theidentification of differential and coordinated gene expression.
J.-M. Claverie (1999)
Hum. Mol. Genet. 8, 1821-1832
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Decrease in Susceptibility Toward Induction of Apoptosis and Alteration in G1 Checkpoint Function as Determinants of Resistance of Human Lung Cancer Cells against the Antisignaling Drug UCN-01 (7-Hydroxystaurosporine).
K. Sugiyama, T. Akiyama, M. Shimizu, T. Tamaoki, C. Courage, A. Gescher, and S. Akinaga (1999)
Cancer Res. 59, 4406-4412
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FJ5002: A Potent Telomerase Inhibitor Identified by Exploiting the Disease-oriented Screening Program with COMPARE Analysis.
I. Naasani, H. Seimiya, T. Yamori, and T. Tsuruo (1999)
Cancer Res. 59, 4004-4011
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Broad patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays.
U. Alon, N. Barkai, D. A. Notterman, K. Gish, S. Ybarra, D. Mack, and A. J. Levine (1999)
PNAS 96, 6745-6750
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Proteasome Inhibitors: A Novel Class of Potent and Effective Antitumor Agents.
J. Adams, V. J. Palombella, E. A. Sausville, J. Johnson, A. Destree, D. D. Lazarus, J. Maas, C. S. Pien, S. Prakash, and P. J. Elliott (1999)
Cancer Res. 59, 2615-2622
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Apoptosis, p53, and Tumor Cell Sensitivity to Anticancer Agents.
J. M. Brown and B. G. Wouters (1999)
Cancer Res. 59, 1391-1399
   Abstract »    Full Text »    PDF »


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