PNAs as Novel Cancer Therapeutics

  • Luca Mologni
  • Carlo Gambacorti-Passerini
Part of the Medical Intelligence Unit book series (MIUN)


Peptide nucleic acid (PNA) is a hybrid compound with nucleoside bases linked to a peptide-like amide backbone. PNA is capable of sequence-specific base pairing and forms highly stable double and triple helices with natural nucleic acids (DNA, RNA). PNA forms stable hydrogen bonds and is resistant to degradation by nudeases and proteases. Because of these physicochemical properties, PNA has attracted great attention, since its first description in 1991, as a potential gene-specific drug and a versatile molecular biology tool. More and more laboratories are working with PNA and the number of applications in which PNA proves useful continues to increase.

In this chapter, we describe aspects of the biochemistry of peptide nucleic acids and their use as a molecular biology reagent, and then focus on the antisense and anti-gene activity of PNA, with special reference to studies of medical interest, in particular in the PML/RARα and the bcl-2 systems.


Peptide Nucleic Acid Cancer Therapeutics Antisense ODNs Galanin Receptor Peptide Nucleic Acid Probe 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Dolnick BJ. Naturally occurring antisense RNA. Pharmacol Ther 1997; 75:179–84.PubMedCrossRefGoogle Scholar
  2. 2.
    Stephenson ML, Zamecnik PC. Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc Natl Acad Sci USA 1978; 75:285–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Izant JG, Weintraub H. Inhibition of thymidine kinase gene expression by anti-sense RNA: A molecular approach to genetic analysis. Cell 1984; 36:1007–15.PubMedCrossRefGoogle Scholar
  4. 4.
    Lebedeva I, Stein CA. Antisense oligonucleotides: Promise and reality. Annu Rev Pharmacol Toxicol 2001; 41:403–19.PubMedCrossRefGoogle Scholar
  5. 5.
    Agrawal S, Kandimalla ER. Antisense therapeutics: Is it as simple as complementary base recognition? Mol Med Today 2000; 6:72–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Levin AA. A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim Biophys Acta 1999; 1489:69–84.PubMedGoogle Scholar
  7. 7.
    Crooke ST, Bennett CF. Progress in antisense oligonucleotide therapeutics. Annu Rev Pharmacol Toxicol 1996; 36:107–29.PubMedCrossRefGoogle Scholar
  8. 8.
    Nielsen PE, Egholm M, Berg RH et al. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science 1991; 254:1497–500.PubMedCrossRefGoogle Scholar
  9. 9.
    Egholm M et al. PNA hybridizes to complementary oligonucleotides obeying the Watson-Crick hydrogen-bonding rules. Nature 1993; 365:566–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Giesen U et al. A formula for thermal stability (Tm) prediction of PNA/DNA duplexes. Nucleic Acids Res 1998; 26:5004–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Jensen KK, Orum H, Nielsen PE et al. Kinetics for hybridization of peptide nucleic acids (PNA) with DNA and RNA studied with the BIAcore technique. Biochemistry 1997; 36:5072–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Peffer NJ et al. Strand-invasion of duplex DNA by peptide nucleic acid oligomers. Proc Natl Acad Sci USA 1993; 90:10648–52.PubMedCrossRefGoogle Scholar
  13. 13.
    Demidov VV, Yavnilovich MV, Belotserkovskii BP et al. Kinetics and mechanism of polyamide ("peptide") nucleic acid binding to duplex DNA. Proc Natl Acad Sci USA 1995; 92:2637–41.PubMedCrossRefGoogle Scholar
  14. 14.
    Cherny DY et al. DNA unwinding upon strand-displacement binding of a thymine-substituted polyamide to double-stranded DNA. Proc Natl Acad Sci USA 1993; 90:1667–70.PubMedCrossRefGoogle Scholar
  15. 15.
    Nielsen PE, Egholm M, Buchardt O. Evidence for (PNA)2/DNA triplex structure upon binding of PNA to dsDNA by strand displacement. J Mol Recognit 1994; 7:165–70.PubMedCrossRefGoogle Scholar
  16. 16.
    Demidov VV et al. Stability of peptide nucleic acids in human serum and cellular extracts. Biochem Pharmacol 1994; 48:1310–3.PubMedCrossRefGoogle Scholar
  17. 17.
    Mardirossian G et al. In vivo hybridization of technetium-99m-labeled peptide nucleic acid (PNA). J Nucl Med 1997; 38:907–13.PubMedGoogle Scholar
  18. 18.
    Brown SC, Thomson SA, Veal JM et al. NMR solution structure of a peptide nucleic acid complexed with RNA. Science 1994; 265:777–80.PubMedCrossRefGoogle Scholar
  19. 19.
    Rasmussen H, Kastrup JS, Nielsen JN et al. Crystal structure of a peptide nucleic acid (PNA) duplex at 1.7 A resolution. Nat Struct Biol 1997; 4:98–101.PubMedCrossRefGoogle Scholar
  20. 20.
    Leijon M et al. Structural characterization of PNA-DNA duplexes by NMR. Evidence for DNA in a B-like conformation. Biochemistry 1994; 33:9820–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Eriksson M, Nielsen PE. Solution structure of a peptide nucleic acid-DNA duplex. Nat Struct Biol 1996; 3:410–3.PubMedCrossRefGoogle Scholar
  22. 22.
    Betts L, Josey JA, Veal JM et al. A nucleic acid triple helix formed by a peptide nucleic acid-DNA complex. Science 1995; 270:1838–41.PubMedCrossRefGoogle Scholar
  23. 23.
    Wittung P, Nielsen PE, Buchardt O et al. DNA-like double helix formed by peptide nucleic acid. Nature 1994; 368:561–3.PubMedCrossRefGoogle Scholar
  24. 24.
    Perry-O’Keefe H, Yao XW, Coull JM et al. Peptide nucleic acid pregel hybridization: An alternative to southern hybridization. Proc Natl Acad Sci USA 1996; 93:14670–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Murakami T et al. A novel method for detecting HIV-1 by nonradioactive in situ hybridization: Application of a peptide nucleic acid probe and catalysed signal amplification. J Pathol 2001; 194:130–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Perry-O’Keefe H et al. Filter-based PNA in situ hybridization for rapid detection, identification and enumeration of specific micro-organisms. J Appl Microbiol 2001; 90:180–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Uhlmann V et al. Improved in situ detection method for telomeric tandem repeats in metaphase spreads and interphase nuclei. Mol Pathol 2000; 53:48–50.PubMedCrossRefGoogle Scholar
  28. 28.
    Fomina J, Darroudi F, Boei JJ et al. Discrimination between complete and incomplete chromosome exchanges in X-irradiated human lymphocytes using FISH with pancentromeric and chromosome specific DNA probes in combination with telomeric PNA probe. Int J Radiat Biol 2000; 76:807–13.PubMedCrossRefGoogle Scholar
  29. 29.
    Boei JJ, Vermeulen S, Natarajan AT. Analysis of radiation-induced chromosomal aberrations using telomeric and centromeric PNA probes. Int J Radiat Biol 2000; 76:163–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Taneja KL, Chavez EA, Coull J et al. Multicolor fluorescence in situ hybridization with peptide nucleic acid probes for enumeration of specific chromosomes in human cells. Genes Chromosomes Cancer 2001; 30:57–63.PubMedCrossRefGoogle Scholar
  31. 31.
    Oyama M et al. Detection of toxic chemicals with high sensitivity by measuring the quantity of induced P450 mRNAs based on surface plasmon resonance. Biotechnol Bioeng 2000; 71:217–22.PubMedCrossRefGoogle Scholar
  32. 32.
    Burgener M, Sanger M, Candrian U. Synthesis of a stable and specific surface plasmon resonance biosensor surface employing covalently immobilized peptide nucleic acids. Bioconjug Chem 2000; 11:749–54.PubMedCrossRefGoogle Scholar
  33. 33.
    Jain KK. Applications of biochip and microarray systems in pharmacogenomics. Pharmacogenomics 2000; 1:289–307.PubMedCrossRefGoogle Scholar
  34. 34.
    Orum H et al. Sequence-specific purification of nucleic acids by PNA-controlled hybrid selection. Biotechniques 1995; 19:472–80.PubMedGoogle Scholar
  35. 35.
    Chandler DP et al. Affinity purification of DNA and RNA from environmental samples with peptide nucleic acid clamps. Appl Environ Microbiol 2000; 66:3438–45.PubMedCrossRefGoogle Scholar
  36. 36.
    Stender H et al. Rapid detection, identification, and enumeration of Pseudomonas aeruginosa in bottled water using peptide nucleic acid probes. J Microbiol Methods 2000; 42:245–53.PubMedCrossRefGoogle Scholar
  37. 37.
    Svanvik N, Westman G, Wang D et al. Light-up probes: Thiazole orange-conjugated peptide nucleic acid for detection of target nucleic acid in homogeneous solution. Anal Biochem 2000; 281:26–35.PubMedCrossRefGoogle Scholar
  38. 38.
    Igloi GL. Automated detection of point mutations by electrophoresis in peptide-nucleic acid-containing gels. Biotechniques 1999; 27:798–800, 802, 804 passim.PubMedGoogle Scholar
  39. 39.
    Griffin TJ, Tang W, Smith LM. Genetic analysis by peptide nucleic acid affinity MALDI-TOF mass spectrometry. Nat Biotechnol 1997; 15:1368–72.PubMedCrossRefGoogle Scholar
  40. 40.
    Chen C, Hong YK, Ontiveros SD et al. Single base discrimination of CENP-B repeats on mouse and human Chromosomes with PNA-FISH. Mamm Genome 1999; 10:13–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Orum H et al. Single base pair mutation analysis by PNA directed PCR clamping. Nucleic Acids Res 1993; 21:5332–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Rhodes CH, Honsinger C, Porter DM et al. Analysis of the allele-specific PCR method for the detection of neoplastic disease. Diagn Mol Pathol 1997; 6:49–57.PubMedCrossRefGoogle Scholar
  43. 43.
    Murdock DG, Christacos NC, Wallace DC. The age-related accumulation of a mitochondrial DNA control region mutation in muscle, but not brain, detected by a sensitive PNA-directed PCR clamping based method. Nucleic Acids Res 2000; 28:4350–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Demers DB, Curry ET, Egholm M et al. Enhanced PCR amplification of VNTR locus D1S80 using peptide nucleic acid (PNA). Nucleic Acids Res 1995; 23:3050–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Veselkov AG, Demidov VV, Nielson PE et al. A new class of genome rare cutters. Nucleic Acids Res 1996; 24:2483–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Demidov V, Frank-Kamenetskii MD, Egholm M et al. Sequence selective double strand DNA cleavage by peptide nucleic acid (PNA) targeting using nuclease S1. Nucleic Acids Res 1993; 21:2103–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Demidov VV et al. Electron microscopy mapping of oligopurine tracts in duplex DNA by peptide nucleic acid targeting. Nucleic Acids Res 1994; 22:5218–22.PubMedCrossRefGoogle Scholar
  48. 48.
    Nielsen PE, Egholm M, Berg RH et al. Sequence specific inhibition of DNA restriction enzyme cleavage by PNA. Nucleic Acids Res 1993; 21:197–200.PubMedCrossRefGoogle Scholar
  49. 49.
    Schmidt JG, Nielsen PE, Orgel LE. Information transfer from peptide nucleic acids to RNA by template-directed syntheses. Nucleic Acids Res 1997; 25:4797–802.PubMedCrossRefGoogle Scholar
  50. 50.
    Schmidt JG, Christensen L, Nielsen PE et al. Information transfer from DNA to peptide nucleic acids by template-directed syntheses. Nucleic Acids Res 1997; 25:4792–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Bohler C, Nielsen PE, Orgel LE. Template switching between PNA and RNA oligonucleotides. Nature 1995; 376:578–81.PubMedCrossRefGoogle Scholar
  52. 52.
    Nielsen PE. Peptide nucleic acid (PNA): A model structure for the primordial genetic material? Orig Life Evol Biosph 1993; 23:323–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Nelson KE, Levy M, Miller SL. Peptide nucleic acids rather than RNA may have been the first genetic molecule. Proc Natl Acad Sci USA 2000; 97:3868–71.PubMedCrossRefGoogle Scholar
  54. 54.
    Hanvey JC et al. Antisense and antigene properties of peptide nucleic acids. Science 1992; 258:1481–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Knudsen H, Nielsen PE. Antisense properties of duplex-and triplex-forming PNAs. Nucleic Acids Res 1996; 24:494–500.PubMedCrossRefGoogle Scholar
  56. 56.
    Gambacorti-Passerini C et al. In vitro transcription and translation inhibition by anti-promyelocytic leukemia (PML)/retinoic acid receptor alpha and anti-PML peptide nucleic acid. Blood 1996; 88:1411–7.PubMedGoogle Scholar
  57. 57.
    Mologni L, leCoutre P, Nielsen PE et al. Additive antisense effects of different PNAs on the in vitro translation of the PML/RARalpha gene. Nucleic Acids Res 1998; 26:1934–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Mologni L, Nielsen PE, Gambacorti-Passerini C. In vitro transcriptional and translational block of the bcl-2 gene operated by peptide nucleic acid. Biochem Biophys Res Commun 1999; 264:537–43.PubMedCrossRefGoogle Scholar
  59. 59.
    Giovine M et al. Synthesis and characterization of a specific peptide nucleic acid that inhibits expression of inducible NO synthase. FEBS Lett 1998; 426:33–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Gee JE et al. Assessment of high-affinity hybridization, RNase H cleavage, and covalent linkage in translation arrest by antisense oligonucleotides. Antisense Nucleic Acid Drug Dev 1998; 8:103–11.PubMedGoogle Scholar
  61. 61.
    Dias N et al. Antisense PNA tridecamers targeted to the coding region of Haras mRNA arrest polypeptide chain elongation. J Mol Biol 1999; 294:403–16.PubMedCrossRefGoogle Scholar
  62. 62.
    Tsujimoto Y, Cossman J, Jaffe E et al. Involvement of the bcl-2 gene in human follicular lymphoma. Science 1985; 228:1440–3.PubMedCrossRefGoogle Scholar
  63. 63.
    Bonham MA et al. An assessment of the antisense properties of RNase H-competent and steric-blocking oligomers. Nucleic Acids Res 1995; 23:1197–203.PubMedCrossRefGoogle Scholar
  64. 64.
    Nielsen PE, Egholm M, Buchardt O. Sequence-specific transcription arrest by peptide nucleic acid bound to the DNA template strand. Gene 1994; 149:139–45.PubMedCrossRefGoogle Scholar
  65. 65.
    Tomac S et al. Ionic effects on the stability and conformation of peptide nucleic acid complexes. J Am Chem Soc 1996;118:5544–5552CrossRefGoogle Scholar
  66. 66.
    Bentin T, Nielsen PE. Enhanced peptide nucleic acid binding to supercoiled DNA: Possible implications for DNA "breathing" dynamics. Biochemistry 1996; 35:8863–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Egholm M et al. Efficient pH-independent sequence-specific DNA binding by pseudoisocytosine-containing bis-PNA. Nucleic Acids Res 1995; 23:217–22.PubMedCrossRefGoogle Scholar
  68. 68.
    Vickers TA, Griffith MC, Ramasamy K et al. Inhibition of NF-kappa B specific transcriptional activation by PNA strand invasion. Nucleic Acids Res 1995; 23:3003–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Praseuth D et al. Peptide nucleic acids directed to the promoter of the alpha-chain of the interleukin-2 receptor. Biochim Biophys Acta 1996; 1309:226–38.PubMedGoogle Scholar
  70. 70.
    Taylor RW, Chinnery PF, Turnbull DM et al. Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids. Nat Genet 1997; 15:212–5.PubMedCrossRefGoogle Scholar
  71. 71.
    Kurg R, Langel U, Ustav M. Inhibition of the bovine papillomavirus E2 protein activity by peptide nucleic acid. Virus Res 2000; 66:39–50.PubMedCrossRefGoogle Scholar
  72. 72.
    Norton JC, Piatyszek MA, Wright WE et al. Inhibition of human telomerase activity by peptide nucleic acids. Nat Biotechnol 1996; 14:615–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Hamilton SE et al. Identification of determinants for inhibitor binding within the RNA active site of human telomerase using PNA scanning. Biochemistry 1997; 36:11873–80.PubMedCrossRefGoogle Scholar
  74. 74.
    Harley CB et al. Telomerase, cell immortality, and cancer. Cold Spring Harb Symp Quant Biol 1994; 59:307–15.PubMedGoogle Scholar
  75. 75.
    Sei S et al. Identification of a key target sequence to block human immunodeficiency virus type 1 replication within the gag-pol transframe domain. J Virol 2000; 74:4621–33.PubMedCrossRefGoogle Scholar
  76. 76.
    Boulme F et al. Modified (PNA, 2′-O-methyl and phosphoramidate) anti-TAR antisense oligonucleotides as strong and specific inhibitors of in vitro HIV-1 reverse transcription. Nucleic Acids Res 1998; 26:5492–500.PubMedCrossRefGoogle Scholar
  77. 77.
    Farese-Di Giorgio A et al. Synthesis of a new class of HIV-1 inhibitors. Nucleosides Nucleotides 1999; 18:263–75.PubMedGoogle Scholar
  78. 78.
    Mayhood T et al. Inhibition of Tat-mediated transactivation of HIV-1 LTR transcription by polyamide nucleic acid targeted to TAR hairpin element. Biochemistry 2000; 39:11532–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Bastide L, Boehmer PE, Villani G et al. Inhibition of a DNA-helicase by peptide nucleic acids. Nucleic Acids Res 1999; 27:551–4.PubMedCrossRefGoogle Scholar
  80. 80.
    Dieci G, Corradini R, Sforza S et al. Inhibition of RNA polymerase III elongation by a T10 peptide nucleic acid. J Biol Chem 2001; 276:5720–5.PubMedCrossRefGoogle Scholar
  81. 81.
    Wittung P et al. Phospholipid membrane permeability of peptide nucleic acid. FEBS Lett 1995; 375:27–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Boffa LC, Morris PL, Carpaneto EM et al. Invasion of the GAG triplet repeats by a complementary peptide nucleic acid inhibits transcription of the androgen receptor and TATA-binding protein genes and correlates with refolding of an active nucleosome containing a unique AR gene sequence. J Biol Chem 1996; 271:13228–33.PubMedCrossRefGoogle Scholar
  83. 83.
    Herbert B et al. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc Natl Acad Sci USA 1999; 96:14276–81.PubMedCrossRefGoogle Scholar
  84. 84.
    Uhlmann E. Peptide nucleic acids (PNA) and PNA-DNA chimeras: From high binding affinity towards biological function. Biol Chem 1998; 379:1045–52.PubMedGoogle Scholar
  85. 85.
    Faruqi AF, Egholm M, Glazer PM. Peptide nucleic acid-targeted mutagenesis of a chromosomal gene in mouse cells. Proc Natl Acad Sci USA 1998; 95:1398–403.PubMedCrossRefGoogle Scholar
  86. 86.
    Basu S, Wickstrom E. Synthesis and characterization of a peptide nucleic acid conjugated to a D-peptide analog of insulin-like growth factor 1 for increased cellular uptake. Bioconjug Chem 1997; 8:481–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Pardridge WM, Boado RJ, Kang YS. Vector-mediated delivery of a polyamide ("peptide") nucleic acid analogue through the blood-brain barrier in vivo. Proc Natl Acad Sci USA 1995; 92:5592–6.PubMedCrossRefGoogle Scholar
  88. 88.
    Boffa LC et al. Dihydrotestosterone as a selective cellular/nuclear localization vector for anti-gene peptide nucleic acid in prostatic carcinoma cells. Cancer Res 2000; 60:2258–62.PubMedGoogle Scholar
  89. 89.
    Chinnery PF et al. Peptide nucleic acid delivery to human mitochondria. Gene Ther 1999; 6:1919–28.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhang X, Simmons CG, Corey DR. Liver cell specific targeting of peptide nucleic acid oligomers. Bioorg Med Chem Lett 2001; 11:1269–72.PubMedCrossRefGoogle Scholar
  91. 91.
    Scarfi S, Gasparini A, Damonte G et al. Synthesis, uptake, and intracellular metabolism of a hydrophobic tetrapeptide-peptide nucleic acid (PNA)-biotin molecule. Biochem Biophys Res Commun 1997; 236:323–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Mologni L, Marchesi E, Nielsen PE et al. Inhibition of PML/RAR{Alpha} expression in acute promyelocytic leukemia cells by Anti-PML peptide nucleic acid (PNA). Cancer Res 2001; 61:5468–73PubMedGoogle Scholar
  93. 93.
    Ljungstrom T, Knudsen H, Nielsen PE. Cellular uptake of adamantyl conjugated peptide nucleic acids. Bioconjug Chem 1999; 10:965–72.PubMedCrossRefGoogle Scholar
  94. 94.
    Schwarze SR, Hruska KA, Dowdy SF. Protein transduction: Unrestricted delivery into all cells? Trends Cell Biol 2000; 10:290–5.PubMedCrossRefGoogle Scholar
  95. 95.
    Pooga M et al. Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo. Nat Biotechnol 1998; 16:857–61.PubMedCrossRefGoogle Scholar
  96. 96.
    Aldrian-Herrada G et al. A peptide nucleic acid (PNA) is more rapidly internalized in cultured neurons when coupled to a retro-inverso delivery peptide. The antisense activity depresses the target mRNA and protein in magnocellular oxytocin neurons. Nucleic Acids Res 1998; 26:4910–6.PubMedCrossRefGoogle Scholar
  97. 97.
    Cutrona G et al. Effects in live cells of a c-myc anti-gene PNA linked to a nuclear localization signal. Nat Biotechnol 2000; 18:300–3.PubMedCrossRefGoogle Scholar
  98. 98.
    Villa R et al. Inhibition of telomerase activity by a cell-penetrating peptide nucleic acid construct in human melanoma cells. FEBS Lett 2000; 473:241–8.PubMedCrossRefGoogle Scholar
  99. 99.
    Tyler BM et al. Specific gene blockade shows that peptide nucleic acids readily enter neuronal cells in vivo. FEBS Lett 1998; 421:280–4.PubMedCrossRefGoogle Scholar
  100. 100.
    Tyler BM et al. Peptide nucleic acids targeted to the neurotensin receptor and administered i.p. cross the blood-brain barrier and specifically reduce gene expression. Proc Natl Acad Sci USA 1999; 96:7053–8.PubMedCrossRefGoogle Scholar
  101. 101.
    Fraser GL, Holmgren J, Clarke PB et al. Antisense inhibition of delta-opioid receptor gene function in vivo by peptide nucleic acids. Mol Pharmacol 2000; 57:725–31.PubMedGoogle Scholar
  102. 102.
    McMahon BM et al. Intraperitoneal injection of antisense peptide nucleic acids targeted to the mu receptor decreases response to morphine and receptor protein levels in rat brain. Brain Res 2001; 904:345–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Good L, Nielsen PE. Antisense inhibition of gene expression in bacteria by PNA targeted to mRNA. Nat Biotechnol 1998; 16:355–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Good L, Awasthi SK, Dryselius R et al. Bactericidal antisense effects of peptide-PNA conjugates. Nat Biotechnol 2001; 19:360–4.PubMedCrossRefGoogle Scholar
  105. 105.
    Good L, Nielsen PE. Inhibition of translation and bacterial growth by peptide nucleic acid targeted to ribosomal RNA. Proc Natl Acad Sci USA 1998; 95:2073–6.PubMedCrossRefGoogle Scholar
  106. 106.
    Stock RP et al. Inhibition of gene expression in Entamoeba histolytica with antisense peptide nucleic acid oligomers. Nat Biotechnol 2001; 19:231–4.PubMedCrossRefGoogle Scholar
  107. 107.
    Rusckowski M, Qu T, Chang F et al. Pretargeting using peptide nucleic acid. Cancer 1997; 80:2699–705.PubMedCrossRefGoogle Scholar
  108. 107a.
    Liu G, Mang’era K, Liu N et al. Tumor pretargeting in mice using (99m)Tc-labeled morpholino, a DNA analog. J Nucl Med 2002; 43(3):384–91.PubMedGoogle Scholar
  109. 108.
    Malchere C et al. A short phosphodiester window is sufficient to direct RNase H-dependent RNA cleavage by antisense peptide nucleic acid. Antisense Nucleic Acid Drug Dev 2000; 10:463–8.PubMedGoogle Scholar
  110. 109.
    Verheijen JC et al. 2,5-oligoadenylate-peptide nucleic acids (2–5A-PNAs) activate RNase L. Bioorg Med Chem 1999; 7:449–55.PubMedCrossRefGoogle Scholar
  111. 110.
    Puschl A, Tedeschi T, Nielsen PE. Pyrrolidine PNA: A novel conformationally restricted PNA analogue. Org Lett 2000; 2:4161–3.PubMedCrossRefGoogle Scholar
  112. 111.
    D’Costa M, Kumar VA, Ganesh KN. Aminoethylprolyl peptide nucleic acids (aepPNA): Chiral PNA analogues that form highly stable DNA: aepPNA2 triplexes. Org Lett 1999; 1:1513–6.PubMedCrossRefGoogle Scholar
  113. 112.
    Garner P, Dey S, Huang Y et al. Modular nucleic acid surrogates. Solid phase synthesis of alpha-helical peptide nucleic acids (alpha PNAs). Org Lett 1999; 1:403–5.PubMedCrossRefGoogle Scholar
  114. 113.
    Zhang L, Min J. Studies on the synthesis and properties of new PNA analogs consisting of L-and D-lysine backbones. Bioorg Med Chem Lett 1999; 9:2903–8.PubMedCrossRefGoogle Scholar
  115. 114.
    Schutz R et al. Olefinic peptide nucleic acids (OPAs): New aspects of the molecular recognition of DNA by PNA the team at the University of Bern thanks the Swiss National Science Foundation and Novartis Pharma AG, Basel, for generous financial support. Angew Chem Int Ed Engl 2000; 39:1250–1253.PubMedCrossRefGoogle Scholar
  116. 115.
    Rezaei K et al. Intrathecal administration of PNA targeting galanin receptor reduces galanin-mediated inhibitory effect in the rat spinal cord. Neuroreport 2001; 12:317–20.PubMedCrossRefGoogle Scholar

Copyright information

© and Kluwer Academic / Plenum Publishers 2006

Authors and Affiliations

  • Luca Mologni
    • 1
    • 2
  • Carlo Gambacorti-Passerini
    • 3
  1. 1.Department of Clinical MedicineUniversity of Milano-BicoccaMonzaItaly
  2. 2.Department of Experimental OncologyNational Cancer InstituteMilanItaly
  3. 3.Oncogenic Fusion Proteins Unit, Department of Experimental OncologyNational Cancer InstituteMilanItaly

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