Patent 5965352 Issued on October 12, 1999. Estimated Expiration Date: May 8, 2018. Estimated Expiration Date is calculated based on simple USPTO term provisions. It does not account for terminal disclaimers, term adjustments, failure to pay maintenance fees, or other factors which might affect the term of a patent.
435/4, MEASURING OR TESTING PROCESS INVOLVING ENZYMES OR MICRO-ORGANISMS; COMPOSITION OR TEST STRIP THEREFORE; PROCESSES OF FORMING SUCH COMPOSITION OR TEST STRIP435/6, Involving nucleic acid435/7.1, Involving antigen-antibody binding, specific binding protein assay or specific ligand-receptor binding assay435/91.2, Acellular exponential or geometric amplification (e.g., PCR, etc.)436/501, BIOSPECIFIC LIGAND BINDING ASSAY536/23.1, DNA or RNA fragments or modified forms thereof (e.g., genes, etc.)536/24.3, Probes for detection of specific nucleotide sequences or primers for the synthesis of DNA or RNA700/266, Chemical process control or monitoring system708/400Transform
The present invention provides methods for identifying and representing the biological pathways of drug action on a cell by: (i) measuring responses of cellular constituents to graded exposures of the cell to a drug of interest; (ii) measuring the responses of cellular constituents to perturbations in one or more biological pathways of the cell; and (iii) scaling a combination of the measured pathway responses to fit the measured drug responses best according to an objective measure. In alternative embodiments, the present invention also provides for assessing the significance of the identified representation and for verifying that the identified pathways are actual pathway of drug action. In various embodiments, the effects on the cell can be determined by measuring gene expression, protein abundances, protein activities, or a combination of such measurements. In various embodiments, perturbation to a biological pathway in the cell can be made by use of titratable expression systems, use of transfection systems, modification to abundances of pathway RNAs, modifications to abundances of pathway proteins, or modifications to activities of the pathway proteins. The present invention also provides methods for drug development based on the methods for identifying biological pathways of drug action, and methods for representing the biological pathways involved in the effect of an environmental change upon a cell.
Other References
Ecker et al, "Estimation of the chemosensitizing activity of modulators of multi-drug resistance via combined simultaneous analysis of sigmoidal dose response curves", J. Pharm. Pharmacol. 49:305-309, Mar. 1997
Uhlmann et al, "Antisense oligonucleotides: A new therapeutic principle", Chemical Reviews 90(4):543-584, Jun. 1990
Anderson et al., 1994, "Involvement of the protein tyrosine kinase p56Ick in T cell signalling and thymocyte development", Adv. Immunol. 56:151-178
Baudin et al., 1993, "A simple and efficient method for direct gene deletion in Saccharomyces cerevisiae", Nucl. Acids Res. 21:3329-3330
Belshaw et al., 1996, "Controlling protein association and subcellular localization with a synthetic ligand that induces heterodimerization of proteins", Proc. Natl. Acad. Sci. USA 93:4604-4607
Biocca, 1995, "Intracellular immunization: antibody targeting to subcellular compartments", Trends in Cell Biology 5:248-253
Blanchard et al., 1996, "Sequence to array: probing the genome's secrets", Nature Biotechnology 14:1649
Chee et al., 1996, "Accessing genetic information with high-density DNA arrays", Science 274:610-614
Cotten and Birnstiel, 1989, "Ribozyme mediated destruction of RNA in vivo", EMBO J. 8:3861-3866
Dohmen et al., 1994, "Heat-inducible degron: a method for constructing temperature-sensitive mutants", Science 263:1273-1276
Gari et al., 1997, "A set of vectors with a tetracycline-regulatable promoter system for modulated gene expression in Saccharomyces crevisiae", Yeast 13:837-848
Goffreau et al., 1996, "Life with 6000 genes", Science 274:546-567
Gossen and Bujard, 1992, "Tight control of gene expression in mammalian cells by tetracycline-responsive promoters", Proc. Natl. Acad. Sci. USA 89:5547-5551
Gossen et al., 1995, "Transcriptional activation by tetracyclines in mammalian cells" Science 268:1766-1769
Guo et al., 1994, "Direct fluorescence analysis of genetic polymorphisms by hybridization with oligonucleotide arrays on glass supports", Nucl. Acids Res. 22:5456-5465
Hanke et al., 1996, "Discovery of a novel, protent, and Src family-selective tyrosine kinase inhibitor", J. Biol. Chem. 271:695-701
Hartwell et al., 1997, "Integrating genetic approaches into the discovery of anticancer drugs", Science 278:1064-1068
Hayden et al., 1997, "Antibody engineering", Curr. Opin. Immunol. 9:201-212
Herskowitz, 1987, "Functional inactivation of genes by dominant negative mutations", Nature 329:219-222
Hoffmann et al., 1997, "A novel tetracycline-dependent expression vector with low basal expression and potent regulatory properties in various mammalian cell lines" Nucl. Acids Res. 25:1078-1079
Johnston and Davis, 1984, "Sequences that regulate the divergent GAL1-GAL10 promoter in Saccharomyces cerevisiae", Mol. Cell. Biol. 4:1440-1448
Kerjan et al., 1986, "Nucleotide sequence of Saccharomyces cerevisiae MET25 gene", Nucl. Acids Res. 14:7861-7871
Lander, 1996, "The new genomics: Global views of biology", Science 274:536-539
Lennon and Lehrach, 1991, "Hybridization analyses of arrayed cDNA libraries" TIG 7:314-317
Mascorro-Gallardo et al., 1996, "Construction of a CUP1 promoter-based vector to modulate gene expression in Saccharomyces cerevisiae", Gene 172:169-170
Matheos et al., 1997, "Tcn1p/Crz1p, a calcineurin-dependent transcription factor that differentially regulates gene expression in Saccharomyces cerevisiae", Genes & Dev. 11:3445-3458
McAdams and Shapiro, 1995, "Circuit simulation of genetic networks", Science 269:650-656
Mikulecky, 1990, "Modeling intestinal absorption and other nutrition-related processes using PSPICE and STELLA", J. Ped. Gastroenterol. Nutr. 11:7-20
Mounts and Liebman, 1997, "Qualitative modeling of normal blood coagulation and its pathological states using stochastic activity networks", Int. J. Biol. Macromolecules 20:265-281
Murmberg et al., 1994, "Regulatable promoters of Saccharomyces cerevisiae: Comparison of transcriptional activity and their use for heterologous expression", Nucl. Acids. Res. 22:5767-5768
Nguyen et al., 1995, "Differential gene expression in the murine thymus assayed by quantitative hybridization of arrayed cDNA clones", Genomics 29:207-216
No et al., 1996, "Ecdysone-inducible gene expression in mammalian cells and transgenic mice", Proc. Natl. Acad. Sci. USA 93:3346-3351
Nocka et al., 1990, "Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W", EMBO J. 9:1805-1813
Oliff and Friend, 1997, "Cancer, principles & practice of oncology, molecular targets for drug development", Mol. Pharmacol. 68:3115-3125
Perimutter and Alberola-IIa, 1996, "The use of dominant-negative mutations to elucidate signal transduction pathways in lymphocytes", Curr. Opin. Immunol. 8:285-290
Polyak et al., 1997, "A model for p53-induced apoptosis", Nature 389:300-306
Reinitz and Sharp, 1995, "Mechanism of eve stripe formation", Mech. Dev. 49:133-158
Schena, 1996, "Genome analysis with gene expression microarrays", BioEssays 18:427
Schena et al., 1996, "Parallel human genome analysis: microarray-based expression monitoring of 1000 genes", Proc. Natl. Acad. Sci. USA 93:10614-10619
Schena et al., 1995, "Quantitative monitoring of gene expression patterns with a complementary DNA microarray", Science 270:467-470
Shalon et al., 1996, "A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridization", Genome Research 639-645
Shiue, 1997, "Identification of candidate genes for drug discovery by differential display", Drug Dev. Res. 41:142-159
Shoemaker et al., 1996, "Quantitative phenotypic analysis of yeast deletion mutants using a highly parallel molecular bar-coding strategy", Nature Genetics 14:450-456
Southern, 1996, "DNA chips: analysing sequence by hybridization to oligonucleotides on a large scale", TIG 12:110-115
Spencer, 1996, "Creating conditional mutations in mammals", TIG 12:181-187
Stathopoulos and Cyert,,, 1997, "Calcineurin acts through the CRZ1/TCN1-encoded transcription factor to regulate gene expression in yeast", Genes & Dev. 11:3432-3444
Straus and Weiss, 1992, "Genetic evidence for the involvement of the Ick tyrosine kinase in signal transduction through the T cell antigen receptor", Cell 70:585-593
Thomas et al., 1995, "Dynamical behaviour of biological regulatory networks--I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state", Bull. Math. Biol. 57:247-276
Yuh et al., 1998, "Genomic Cis-regulatory logic: experimental and computational analysis of a sea urchin gene", Science 279:1896-1902
Velculescu et al., 1995, "Serial analysis of gene expression", Science 270:484-487
Zhao et al., 1995, "High-density cDNA filter analysis: a novel approach for large-scale, quantitative analysis of gene expression", Gene 156:207-21