Pharmacologic control of specific gene expression

  • John S. Holcenberg
  • Henry P. Wu
Part of the Cancer Treatment and Research book series (CTAR, volume 58)


Cancer cells proliferate, invade surrounding tissues, and metastasize because they have escaped the normal mechanisms that control these processes [1,2]. Many of the genes that regulate these processes have now been isolated and characterized. Pharmacologic control of the expression of these genes would provide exciting new approaches to cancer chemotherapy.


Herpes Simplex Virus Type Antisense Oligonucleotide Minor Groove Binding Antisense Construct Oligonucleotide Derivative 
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  1. 1.
    Bishop JM. The molecular genetics of cancer. Science 235:305–311, 1987.PubMedCrossRefGoogle Scholar
  2. 2.
    Weinstein IB. The origins of human cancer: molecular mechanisms of carcinogenesis and their implications for cancer prevention and treatment. Cancer Res 48:4135–4143, 1988.PubMedGoogle Scholar
  3. 3.
    Leder A, Pattengale PK, Kuo A, Stewart TA, Leder P. Consequences of widespread deregulation of the c-myc gene in transgenic mice: multiple neoplasms and normal development. Cell 45:485–495, 1986.PubMedCrossRefGoogle Scholar
  4. 4.
    Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, and Leder P. Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell 49:465–475, 1987.PubMedCrossRefGoogle Scholar
  5. 5.
    Rauscher FJ, Cohen DR, Curran T, Bos TJ, Vogt PK, Bohmann D, Tjian R, and Franza BR Jr. Fos-associated protein p39 is the product of the jun proto-oncogene. Science 240:1010–1016, 1988.PubMedCrossRefGoogle Scholar
  6. 6.
    Lippman ME, Dickson RB, Gelmann EP, Rosen N, Knabbe C, Bates S, Bronzert D, Huff K, and Kasid A. Growth regulation of human breast carcinoma occurs through regulated growth factor secretion. J Cell Biochem 35:1–16, 1987.PubMedCrossRefGoogle Scholar
  7. 7.
    Klein G. The approaching era of the tumor suppressor genes. Science 238:1539–1545, 1987.PubMedCrossRefGoogle Scholar
  8. 8.
    Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, and Dryja TP. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Science 323:643–646, 1986.Google Scholar
  9. 9.
    DeCaprio JA, Ludlow JW, Figge J, Shew JY, Huang CM, Lee WH, Marsillo E, Paucha E, and Livingston DM. Large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 54:275–283, 1988.PubMedCrossRefGoogle Scholar
  10. 10.
    Laug WE and Bogenmann E. Plasminogen activator inhibitors in vascular smooth muscle cells. In: The Pharmacology and Toxicology of Proteins, JS Holcenberg and JL Winkelhake (eds). Alan R. Liss, New York, 1987, pp. 325–335.Google Scholar
  11. 11.
    Hashimoto Y and Shudo K. Drugs which interact with DNA. Molecular design of antitumor agents. Life Chem Rep 6:231–265, 1988.Google Scholar
  12. 12.
    Kopka ML, Yoon C, Goodsell D, Pjura P, and Dickerson RE. The molecular origin of DNA-drug specificity in netropsin and distamycin. Proc Natl Acad Sci USA 82:1376–1380, 1985.PubMedCrossRefGoogle Scholar
  13. 13.
    Goodsell D and Dickerson RE. Isohelical analysis of DNA groove-binding drugs. J Med Chem 29:727–733, 1986.PubMedCrossRefGoogle Scholar
  14. 14.
    Woynarowski, JM, McHugh, M, Sigmund, RD, and Beerman, TA. Modulation of topoisomerase II catalytic activity by DNA minor groove binding agents distamycin, Hoechst 33258, and 4’, 6-diamidine-2-phenylindole. Mol Pharmacol 35:177–82, 1989.PubMedGoogle Scholar
  15. 15.
    McHugh, MM, Woynarowski, JM, Sigmund, RD, and Beerman, TA. Effect of minor groove binding drugs on mammalian topoisomerase I activity. Biochem Pharmacol 38: 2323–2328, 1989.PubMedCrossRefGoogle Scholar
  16. 16.
    Dervan P. Design of sequence specific DNA-binding molecules. Science 232:464–471, 1987.CrossRefGoogle Scholar
  17. 17.
    Krowicki K, Balzarini J, DeClercq E, Newman RA, and Lown JW. Novel DNA groove binding alkylators: design, synthesis and biological evaluation. J Med Chem 31:341–345, 1988.PubMedCrossRefGoogle Scholar
  18. 18.
    Moy BC, Petzold GL, Badiner GJ, Kelly RC, Aristoff PA, Adams EG, Li LH, and Bhuyan BK. Characterization of B16 melanoma cells resistant to the CC-1065 analogue U-71,184. Cancer Res 50:2485–2492, 1990.PubMedGoogle Scholar
  19. 19.
    Kohn KW, Hartley JA, and Mattes WB. Mechanisms of DNA sequence selectivity of guanine-N7 positions by nitrogen mustards. Nucleic Acids Res 15:10531–10549, 1987.PubMedCrossRefGoogle Scholar
  20. 20.
    Boutorin AS, Vlassov VV, Kazakov SA, Kutiavin IV, and Podyminogin MA. Complementary addressed reagents carrying EDTA-Fe(II) groups for directed cleavage of single stranded nucleic acids. FEBS Lett 172:43–46, 1984.CrossRefGoogle Scholar
  21. 21.
    Vlassov VV, Gorn VV, Ivanova EM, Kazakov SA, and Mamaev SV. Complementary addressed modification of oligonucleotide d(pGpGpCpGpGpA) with platinum derivative of oligonucleotide d(pTpCpCpGpCpCpTpTpT). FEBS Lett 162:286–289, 1983.CrossRefGoogle Scholar
  22. 22.
    Abramova TV, Vlassov VV, Lebedev AV, and Ryte AS. Complementary addressed modification of nuclear acids with the alkylating derivatives of oligothymidylate ethyl phosphotriesters. FEBS Lett 236:243–245, 1988.PubMedCrossRefGoogle Scholar
  23. 23.
    Moser HE and Dervan PB. Sequence-specific cleavage of double stranded helical DNA by triple helix formation. Science 238:645–650, 1987.PubMedCrossRefGoogle Scholar
  24. 24.
    Rajagopal P and Feigon J. NMR studies of triple-strand formation from the homopurine-homopyrimidine deoxyribonucleotides d(GA)4 and d(TC)4. Biochemistry 28:7859–7870, 1989.PubMedCrossRefGoogle Scholar
  25. 25.
    Francois JC, Saison-Behmoaras T, Chassignol M, Thuong NT, and Helene C. Sequence-specific cleavage of single- and double-stranded DNA by oligonucleotides covalently linked to 1,10-phenanthroline. J Biol Chem 264:5891–5898, 1989.PubMedGoogle Scholar
  26. 26.
    Helene C, Monteray-Garestier T, Saison T, Takasugi M, Toulme JJ, Asseline U, Lancelot G, Maurizot JC, Toulme F, and Thuong NT. Oligonucleotides covalently linked to intercalating agents: a new class of gene regulatory substances. Biochimie 67:777–783, 1985.PubMedCrossRefGoogle Scholar
  27. 27.
    Perrouault L, Asseline U, Rivalle C, Thoung NT, Bisagni E, Giovannangeli C, LeDuon T, and Helene C. Sequence-specific artificial photo-induced endonucleases based on triple helix-formed oligonucleotodes. Nature 344:358–360, 1990.PubMedCrossRefGoogle Scholar
  28. 28.
    Mizuno T, Chou MY, and Inouye M. A unique mechanism regulating gene expression: translational inhibition by a complementary RNA transcript (micRNA). Proc Natl Acad Sci USA 81:1966–1970, 1984.PubMedCrossRefGoogle Scholar
  29. 29.
    Zamecnik PC and Stephenson ML. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligonucleotide. Proc Natl Acad Sci USA 75:280–284, 1978.PubMedCrossRefGoogle Scholar
  30. 30.
    Oligonucleotides: antisense inhibitors of gene expression. In: Topics in Molecular and Structural Biology, JS Cohen (ed). CRC Press, Boca Raton, FL, 1989, p. 255.Google Scholar
  31. 31.
    Stein CA and Cohen JS. Oligonucleotides as inhibitors of gene expression: a review. Cancer Res 48:2659–2668, 1988.PubMedGoogle Scholar
  32. 32.
    Zon G. Oligonucleotide analogues as potential chemotherapeutic agents. Pharmaceutical Res 5:539–549, 1988.CrossRefGoogle Scholar
  33. 33.
    Melton DA. Injected anti-sense RNAs specifically block messenger RNA translation in vivo. Proc Natl Acad Sci USA 82:144–148, 1985.PubMedCrossRefGoogle Scholar
  34. 34.
    Rebagliati MR and Melton DA. Antisense RNA injections in fertilized frog eggs reveal an RNA duplex unwinding activity. Cell 48:599–605, 1987.PubMedCrossRefGoogle Scholar
  35. 35.
    Izant JG and Weintraub H. Inhibition of thymidine kinase gene expression by antisense RNA: a molecular approach to genetic analysis. Cell 36:1007–1015, 1984.PubMedCrossRefGoogle Scholar
  36. 36.
    Izant JG and Weintraub H. Constitutive and conditional suppression of exogenous and endogenous genes by antisense RNA. Science 229:345–352, 1985.PubMedCrossRefGoogle Scholar
  37. 37.
    Kim SK and Wold BJ. Stable reduction of thymidine kinase activity in cells expressing high levels of antisense RNA. Cell 42:129–138, 1985.PubMedCrossRefGoogle Scholar
  38. 38.
    Yokoyama K and Imamoto F. Transcriptional control of the endogenous myc protooncogene by antisense RNA. Proc Natl Acad Sci USA 84:7363–7367, 1987.PubMedCrossRefGoogle Scholar
  39. 39.
    Rosenberg UB, Preiss A, Seifert E, Jackie H, and Knippie DC. Production of phenocopies by Kruppel antisense RNA injection into Drosophila embryos. Nature 313:703–706, 1985.PubMedCrossRefGoogle Scholar
  40. 40.
    Coleman J, Hirashima A, Inokuchi Y, Green PJ, and Inouye M. A novel immune system against bacteriophage infection using complementary RNA (micRNA). Nature 315:601–603, 1985.PubMedCrossRefGoogle Scholar
  41. 41.
    To RY, Booth SC, and Nieman PE. Inhibition of retroviral replication by anti-sense RNA. Mol Cell Biol 6:4758–4762, 1986.PubMedGoogle Scholar
  42. 42.
    Pestka S, Daugherty BL, Jung V, Hotta K, and Pestka RK. Anti-mRNA: specific inhibition of translation of single mRNA molecules. Proc Natl Acad Sci USA 81:7525–7528, 1984.PubMedCrossRefGoogle Scholar
  43. 43.
    Mahler LJ and Dolnick BJ. Specific hybridization arrest of dihydrofolate reductase mRNA in vitro using anti-sense RNA or anti-sense oligonucleotides. Arch Bioch Biophys 253:214–220, 1987.CrossRefGoogle Scholar
  44. 44.
    Shuttleworth J and Colman A. Antisense oligonucleotide-directed cleavage of mRNA in Xenopus oocytes and eggs. EMBO J 7:427–434, 1988.PubMedGoogle Scholar
  45. 45.
    Walder RY and Walder JA. Role of RNase H in hybrid-arrest translation by antisense oligonucleotides. Proc Natl Acad Sci USA 85:5011–5015, 1988.PubMedCrossRefGoogle Scholar
  46. 46.
    Heikkila R, Schwab G, Wickstrom E, Loke SL, Pluznik DH, Watt R, and Neckers LM. A c-myc antisense oligonucleotide inhibits entry into S phase but not progress from G0 to G1. Nature 328:445–449, 1987.PubMedCrossRefGoogle Scholar
  47. 47.
    Jaskulski D, DeRiel JK, Mercer WE, Calabretta B, and Baserga R. Inhibition of cellular proliferation by antisense oligonucleotides to PCNA cyclin. Science 240:1544–1546, 1988.PubMedCrossRefGoogle Scholar
  48. 48.
    Miller PS, McParland KB, Jayaraman K, and Ts’o P. Biochemical and biological effects of nonionic nucleic acid methylphosphonates. Biochemistry 20:1874–1880, 1981.PubMedCrossRefGoogle Scholar
  49. 49.
    Ts’o POP, Miller PS, and Greene JJ. Nucleic acid analogs with targeted delivery as chemotherapeutic agents. In: Development of Target-Oriented Anticancer Drugs, YC Cheng, B Goz and M Minkoff (eds). Raven Press, New York, 1983, pp. 189–206.Google Scholar
  50. 50.
    Smith C, Aurelian L, Reddy M, Miller P, and Ts’o P. Antiviral effect of an oligo(nucleoside methylphosphonate) complementary to the splice junction of herpes simplex virus type I immediate early pre-mRNAs 4 and 5. Proc Natl Acad Sci USA 83:2787–2791, 1986.PubMedCrossRefGoogle Scholar
  51. 51.
    Kean JM, Murakami A, Balke KR, Cushman CD, and Miller PS. Photochemical crosslinking of psoralen-derivatized oligonucleotide methylphosphorates to rabbit globin messenger RNA. Biochemistry 27:9113–9121, 1988.PubMedCrossRefGoogle Scholar
  52. 52.
    Kulka M, Smith CC, Aurelian L, Fishelevich R, Meade K, Miller P and Ts’o POP. Site specificity of the inhibitory effects of oligo (nucleoside methylphosphonates) complementary to the acceptor splice junction of herpes simplex virus type 1 immediate early mRNA 4. Proc Natl Acad Sci USA 86:6868–6872, 1989.PubMedCrossRefGoogle Scholar
  53. 53.
    Vasanthakumar G and Ahmed NK. Modulation of drug resistance in a daunorubicin resistant subline with oligonucleotide methylphosphonates. Cancer Commun 1:225–232, 1989.PubMedGoogle Scholar
  54. 54.
    User Bulletin. Applied Biosystems Separation Systems 44:1–18, 1987.Google Scholar
  55. 55.
    Loke SL, Stein CA, Zhang XH, Mori K, Nakanishi M, Subasinghe C, Cohn JS, and Neckers LM. Characterization of oligonucleotide transport into living cells. Proc Natl Acad Sci USA 86:3474–3478, 1989.PubMedCrossRefGoogle Scholar
  56. 56.
    Marcus-Sekura CJ, Woerner AM, Shinozuka K, Zon G, and Quinnan J. Comparative inhibition of chloroamphenicol acetyltransferase gene expression by antisense oligonucleotide analogues having alkyl phosphotriester, methylphosphonate and phosphorothioate linkages. Nucleic Acids Res 15:5749–5763, 1987.PubMedCrossRefGoogle Scholar
  57. 57.
    Goodchild J, Agrawal S, Civeira MP, Sarin PS, Sun DX, and Zamecnik PC. Inhibition of human immunodeficiency virus replication by antisense oligodeoxynucleotides. Proc Natl Acad Sci USA 85:5507–5511, 1988.PubMedCrossRefGoogle Scholar
  58. 58.
    Sarin PS, Agrawal S, Civiera MP, Goodchild J, Ikeuchi T, and Zamecnik PC. Inhibition of acquired immunodeficiency syndrome virus by oligo-deoxynucleoside methylphosphonates. Proc Natl Acad Sci USA 85:7448–7451, 1988.PubMedCrossRefGoogle Scholar
  59. 59.
    Agrawal S, Goodchild J, Cibiera MP, Thornton AH, Sarin PS, and Zamecnik PC. Oligodeoxynucleoside phosphoramidates and phosphorothioates as inhibitors of human immunodeficiency virus. Proc Natl Acad Sci USA 85:7079–7083, 1988.PubMedCrossRefGoogle Scholar
  60. 60.
    Matsukura M, Shinozuka K, Zon G, Mitsuya H, Teitz M, Cohen JS, and Broder S. Phosphorothioate analogs of oligonucleotides: Inhibitors of replication and cytopathic effects of human immunodeficiency virus. Proc Natl Acad Sci USA 84:7706–7710, 1987.PubMedCrossRefGoogle Scholar
  61. 61.
    Majundar C, Stein CA, Cohen JS, Broder S, and Wilson SH. Step wise mechanism of HIV reverse transcriptase: primer function of phosphorothioate oligonucleotide. Biochemistry 28:1340–1346, 1989.CrossRefGoogle Scholar
  62. 62.
    Gao W, Stein CA, Cohen JS, Outschman GE, and Cheng YC. Effect of phosphorothioate homo-deoxynucleotides on herpes simplex virus type 2-induced DNA polymerase. J Biol Chem 264:11521–11526, 1989.PubMedGoogle Scholar
  63. 63.
    Matsukura M, Zon G, Shinozuka K, Robert-Guroff M, Shimada T, Stein CA, Mitsuya H, Wong-Staal F, Cohen JS, and Broder S. Regulation of viral expression of HIV in vitro by an antisense phosphorothioate oligo-deoxynucleotide against rev (art/trs) in chronically infected cells. Proc Natl Acad Sci USA 86:4244–4248, 1989.PubMedCrossRefGoogle Scholar
  64. 64.
    Agawal S, Ikeuchi T, Sun D, Sarin PS, Konopka A, Maizedl J, and Zamecnik PC. Inhibition of human immunodeficiency virus in early infected and chronically infected cells by antisense oligonucleotide and their phophorothioate analoque. Proc Natl Acad Sci USA 86:7790–7794, 1989.CrossRefGoogle Scholar
  65. 65.
    Cazenave C, Loreau N, Thuong NT, Toulme JJ, and Helene C. Enzymatic amplification of translation of rabbit β-globin mRNA mediated by antimessenger oligonucleotides covalently linked to intercalating agents. Nucleic Acids Res 15:4717–4736, 1987.PubMedCrossRefGoogle Scholar
  66. 66.
    Lemaitre M, Bayard B, and Lebleu B. Specific antiviral activity of a poly(L-lysine)-conjugated oligodeoxyribonucleotide sequence complementary to vesicular stomatitis virus N protein mRNA initiation site. Proc Natl Acad Sci USA 84:648–652, 1987.PubMedCrossRefGoogle Scholar
  67. 67.
    Been MD and Cech TR. One binding site determines sequence specificity of tetrahymena pre-rRNA self-splicing, trans-splicing and RNA enzyme activity. Proc Natl Acad Sci USA 47:207–216, 1987.Google Scholar
  68. 68.
    Herschlag D and Cech TR. DNA cleavage catalysed by the ribozyme from Tetrahymena. Nature 344:405–409, 1990.PubMedCrossRefGoogle Scholar
  69. 69.
    Cameron FH and Jennings PA. Specific gene suppression by engineered ribozyme in monkey cells. Proc Natl Acad Sci USA 86:9139–9143, 1989.PubMedCrossRefGoogle Scholar
  70. 70.
    Chang PS, Cantin EM, Zaia JA, Ladne PA, Stephens DA, Sarver N, and Ross JJ. Ribozyme-mediated site-specific cleavage of the HIV-1 genome. Clin Biotechnol 2:23–31, 1990.Google Scholar
  71. 71.
    Gidoni D, Dynan WS, and Tjian R. Multiple specific contacts between a mammalian transcription factor and its cognate promoters. Nature 312:409–413, 1984.PubMedCrossRefGoogle Scholar
  72. 72.
    McKnight SL and Kingsbury R. Transcriptional control signals of a eukaryotic proteincoding gene. Science 217:316–324, 1982.PubMedCrossRefGoogle Scholar
  73. 73.
    Singh HR, Sen D, Baltimore D, and Sharp PA. A nuclear factor that binds to a conserved sequence motif in transcriptional control elements of immunoglobulin genes. Nature 314: 154–158, 1986.CrossRefGoogle Scholar
  74. 74.
    Davison BL, Egly JM, Mulvihill ER, and Chambon P. Formation of stable preinitiation complexes between eukaryotic class B transcription factors and promoter sequences. Nature 301:680–686, 1983.PubMedCrossRefGoogle Scholar
  75. 75.
    Wu H, Holcenberg JS, Tomich J, Chen J, Jones PA, Huang SH, and Calame KL. Inhibition of in vitro transcription by specific double-stranded oligonucleotides. Gene 89:203–209, 1990.PubMedCrossRefGoogle Scholar
  76. 76.
    Wu L, Rosser DSE, Schmidt MC, and Berk A. A TATA box implicated in EIA transcription activation of a simple adenovirus 2 promoter. Nature 326:512–515, 1987.PubMedCrossRefGoogle Scholar
  77. 77.
    Kadonaga JT, Courey AJ, Ladika J, and Tjian R. Distinct regions of Spl modulate binding and transcriptional activation. Science 242:1566–1570, 1988.PubMedCrossRefGoogle Scholar

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© Kluwer Academic Publishers, Boston. 1992

Authors and Affiliations

  • John S. Holcenberg
  • Henry P. Wu

There are no affiliations available

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