Inhibitors of alternative alleles of genes as a basis for cancer

Details Inhibitors of alternative alleles of genes as a basis for cancer Inhibitors of alternative alleles of genes as a basis for cancer

1997-11-11

2000-04-25

Schwartzman, Robert A.

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

435366, C12Q 168, C12N 508

Patent

active

06054273&

ABSTRACT:
This invention is directed to a therapeutic strategy involving (1) identification of alternative alleles of genes coding for protein vital for cell viability or cell growth and the loss of one of those alleles in cancer cells due to loss of heterozygosity (LOH) and (2) the development of inhibitors with high specificity for the single remaining alternative allele of the vital gene retained by the cancer cell after LOH. The inhibitors of this invention are specific for one alternative allele of a gene that codes for a protein vital to cell viability or cell growth. The targeted gene has two alternative alleles in which the inhibitors of this invention blocks only one of the two alternative alleles, still present in the cancer cells. Exposure to the inhibitor inhibits or kills cancer cells which have undergone LOH. Protein is still capable of being expressed in the normal cells exposed to the inhibitor by the unblocked alternative allele. This differential effect of the inhibitor on cancer cells and normal cells accounts for the high therapeutic index of the inhibitors of this invention when used as antineoplastic agents.

REFERENCES:
Osband et al. (Jun. 1990) Problems in the investigational study and clinical use of cancer immunotherapy. Immunol. Today 11:193-195.
Hird et al. (1990) Immunotherapy with monoclonal antibodies. In "Genes and Cancer", D. Carney, K. Sikora (Eds.) John Wiley & Sons Ltd. pp. 183-189.
Harris et al. (Feb. 1993) Therapeutic antibodies-the coming of age. Trends Biotechnol. 11:42-44.
Branch (Feb. 1998) A good antisense molecule is hard to find. Trends Biol. Sci. 23:45-50.
Stull et al. (Apr. 1995) Antigene, ribozyme and aptamer nucleic acid drugs: progress and prospects. Pharm. Res. 12:465-483.
Rojanasakul (1996) Antisense oligonucleotide therapeutics: delivery and targeting. Adv. Drug Del. Rev. 18:115-131.
Gura (Nov. 1997) Systems for identifying new drugs are often faulty. Science 278:1041-1042.
Abbas, Lichtman and Pober, Cellular and Molecular Immunology, W.B. Saunders Co. (1991).
Bolis et al., "A Machine Learning Approach to Computer-Aided Molecular Design," J. Computer-Aided Molecular Design 5:617-628 (1991).
Buetler, E., Clinical Biochemistry 24:293-300 (1991).
Cameron and Jennings, "Specific gene suppression by engineered ribozymes in monkey cells," PNAS USA 86:9139-9143 (1989).
Coligan, J.E., et al. "Current Protocols in Immunology," Wiley Interscience, NY (1990).
Cooper, D. et al., Human Genetics 69:201-205 (1985).
Cotton and Birnstiel, "Ribozyme mediated destruction of RNA in vivo," EMBO J. 8:3861-3866 (1989).
Dixon, J., "Computer-aided Drug Design: Getting the Best Results," Trends in Biotechnology, 10:357-363 (1992).
Flach, J.E., et al., Mol. Biol. Med. 7:365-369 (1990).
Freshney, I.R., "Culture of Animal Cells: A Manual of Basic Technique," Alan R. Liss, Inc., NY, NY (1983).
Gerlach and Young, "ribozymes for the Control of Gene Activity in vivo," Antisense Nucleic Acids and Proteins: Fundamentals and Applications, edited by J.N.M. Mol & A.R. van der Drol. Marcel Kekker, Inc. NY, Chapter 8 (1990).
Harlow, E. and D. Lane, "Antibodies," Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1988).
Hilbert et al., "Receptor 3D-Models and Drug Design," Therapie (Paris) 46:445-451 (1991).
Holzmayer, T.A., et al., Nucleic Acids Research 20(4):711-717 (1992).
Inouye, Antisense RNA; its functions and applications in gene regulation--a review, Gene 72:25-34 (1988).
Keen, J., D. Lester, C. Inglehearn, A. Curtis and S. Bhattacharya, "Rapid Detection of Single Base Mismatches as Heteroduplexes on Hydrolink Gels," Trends in Genetics 7:5 (1991).
Klopman, G., "Multicase 1: A Hierarchical ComputerAutomated Structure Evaluation Program," Quantitative Structure-Activity Relationships 10:350-358 (1991).
Kuntz, I., "Structure-Based Strategies for Drug Design and Discovery," Science 257:1078-1082 (1992).
Lasko, D., et al., Ann. Rev. Genetics 25: 281-314 (1991).
Lawrence and Davis, "CLIX: A Search Algorithm for Finding Novel Ligands Capable of Binding Proteins of Known Three-Dimensional Structure," Proteins Structure Functional Genetics 12:31-41 (1992).
Masters and Attardi, "The nucleotide sequence of the cDNA coding for the human dihydrofolic acid reductase," Gene 21:59-63 (1983).
Masters et al., "A Human Dihydrofolatte Reductase Pseudogene and its Relationship to the Multiple Forms of Specific Messenger RNA," J. Mol. Bio. 167:23-36 (1983).
McCafferty, et al., Nature 348:552 (1990).
McClelland, Kuhn & Ruddle, "The Human Transferrin Receptor Gene: Genomic Organization and the Complete Primary Structure of the Receptor deduced from a cDNA Sequence," Cell 39:267-274 (1994).
Miller and Ts'O, Anti-Cancer Drug Des. 2:11-128 (1987).
Mitelman, F., Catalog of Chromosome Aberrations in Cancer New York: Liss (1988).
Monia, et al., "Selective Inhibition of Mutant Ha-ras mRNA Expression by Antisense Oligonucleotides," J. Biol. Chem., 267(28):19954-19962 (1992).
Morandni et al., "Multiple Forms of Human Dihydrofolate Reductase Messenger RNA," J. Mol. Bio. 156:583-607 (1982).
Myers, Maniatis, and Lerman, Methods Enzymol. 155:501-527 (1987).
Orita, et al., Rapid and Sensitive Detection of Point Mutations and DNA Polymorphisms Using the Polymerase Chain Reaction, Genomics 5:874-879 (1989).
Pelletier, J., et al., Cell 67:437-447 (1991).
Piper et al., "Studies Aided by Molecular Graphics of Effects of Structural Modifications on the Binding of Antifolate Inhibitors to Human Dihydrofolate Reductase," Proc. Am. Assoc. Cancer Res. Annual Meeting 33:412 (1992).
Sambrook, Fritsch, Maniatis, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY p. 7.19-7.22 (1989).
Sandberg, The Chromosomes in Human Cancer and Leukemia, New York: Elsevier (1980).
Sato, J.K., et al., Proceedings of AACR, vol. 26, Abstract No. 903, p. 229 (1985).
Sato, J.K., et al., Proceedings of AACR, vol. 27, Abstract No. 1023, p. 258 (1986).
Schneider, C., et al., Nature, 311:675-678 (1984).
Scott, J.K. ans G.P. Smith, "Searching for Peptide Ligands with an Epitope Library," Sciences, 249:386-390 (1990).
Seizinger, B.R., et al., Cytogenet. Cell Genetics, 58: 1080-1096 (1991).
Silverman, R., The Organic Chemistry of Drug Design and Drug Action, Academic Press (1992).
Taetle, R., et al., Cancer Research, 46:1759-1763 (1986).
Testa, U., et al., Normal and neoplastic Blood Cells:From Genes to Therapy, Annals of the New York Academy of Sciences, 511:131-137 (1987).
Toulme and Helene, "Antimessenger oligodeoxyribonucleotides; an alternative to antisense RNS for artificial regulation of gene expression--a review," Gene 72:51-58 (1988).
Trojan, J., et al., Science 259:94-97 (1993).
Trowbridge, I.S., et al., Proc. Natl. Acad. Sci., USA 79:1175-1179 (1982).

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