Receptor-Specific Targeting with Complementary Peptide Nucleic Acids Conjugated to Peptide Analogs and Radionuclides

  • Eric Wickstrom
  • Mathew L. Thakur
  • Edward R. Sauter
Part of the Medical Intelligence Unit book series (MIUN)


Genomic sequencing makes it possible to identify all the genes of an organism, now including Homo sapiens. Yet measurement of the expression of each gene of interest still presents a daunting prospect. Northern blots, RNase protection assays, as well as microarrays and related technologies permit measurement of gene expression in total RNA extracted from cultured cells or tissue samples. It would be most valuable, however, to quantitate gene expression noninvasively in living cells and tissues. Unfortunately, no reliable method has been available to measure levels of specific mRNAs in vivo. Peptide nucleic acids (PNAs) display superior ruggedness and hybridization properties as a diagnostic tool for gene expres-sion, and could be used for this purpose. On the down side, they are negligibly internalized by normal or malignant cells in the absence of conjugated ligands. Nevertheless, we have observed that Tc-99m-peptides can delineate tumors, and PNA-peptides designed to bind to IGF-1 receptors on malignant cells are taken up specifically and concentrated in nuclei. We have postulated that antisense Tc-99m-PNA-peptides will be taken up by human cancer cells, will hybridize to complementary mRNA targets, and will permit scintigraphic imaging of oncogene mRNAs in human cancer xenografts in a mouse model. The oncogenes cyclin D1, ERBB2, c-MYC, K-RAS, and tumor suppressor p53 are being probed initially. These experiments pro-vide a proof-of-principle for noninvasive detection of oncogene expression in living cells and tissues. This scintigraphic imaging technique should be applicable to any particular gene of interest in a cell or tissue type with characteristic receptors.


Peptide Nucleic Acid Organotypic Culture Scintigraphic Imaging Herpes Simplex Virus Thymidine Kinase Human Cancer Xenograft 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Adelaide J, Monges G, Derderian C et al. Oesophageal cancer and amplification of the human cyclin D gene CCND1/PRAD1. Br J Cancer 1995; 71:64–8.PubMedGoogle Scholar
  2. 2.
    Agrawal S. Antisense oligonucleotides: Towards clinical trials. Trends In Biotechnology 1996a; 14:376–87.PubMedCrossRefGoogle Scholar
  3. 3.
    Agrawal S. Antisense Therapeutics. In: Walker JM, ed. Methods in Molecular Medicine. Totowa, NJ: Humana Press, 1996b:10.Google Scholar
  4. 4.
    Agrawal S, Jiang Z, Zhao Q et al. Mixed-backbone oligonucleotides as second generation antisense oligonucleotides: In vitro and in vivo studies. Proceedings of the National Academy of Sciences of the United States of America 1997; 94:2620–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Albericio F, Hammer RP, Garcia-Echeverria C et al. Cyclization of disulfide-containing peptides in solid-phase synthesis. Int J Pept Protein Res 1991; 37:402–13.PubMedCrossRefGoogle Scholar
  6. 6.
    Alimandi M, Romano A, Curia M C et al. Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. Oncogene 1995; 10:1813–21.PubMedGoogle Scholar
  7. 7.
    Almoguera C, Shibata D, Forrester K et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988; 53:549–54.PubMedCrossRefGoogle Scholar
  8. 8.
    American Cancer Society 2001.Google Scholar
  9. 9.
    Andrews DW, Resnicoff M, Flanders AE et al. Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas. J Clin Oncol 2001; 19:2189–200.PubMedGoogle Scholar
  10. 10.
    Aoki K, Yoshida T, Sugimura T et al. Liposome-mediated in vivo gene transfer of antisense K-ras construct inhibits pancreatic tumor dissemination in the murine peritoneal cavity. Cancer Res 1995; 55:3810–6.PubMedGoogle Scholar
  11. 11.
    Aramini JM, Germann MW. NMR studies of DNA duplexes containing alpha-anomeric nucleotides and polarity reversals. Biochem Cell Biol 1998; 76:403–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Arany I, Yen A, Tyring SK. p53, WAF1/CIP1 and mdm2 expression in skin lesions associated with human papillomavirus and human immunodeficiency virus. Anticancer Res 1997; 17:1281–5.PubMedGoogle Scholar
  13. 13.
    Armengol G, Knuutila S, Lluis F et al. DNA copy number changes and evaluation of MYC, IGF1R, and FES amplification in xenografts of pancreatic adenocarcinoma. Cancer Genet Cytogenet 2000; 116:133–41.PubMedCrossRefGoogle Scholar
  14. 14.
    Arnold A, Kim HG, Gaz RD et al. Molecular cloning and chromosomal mapping of DNA rear-ranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest 1989; 83:2034–40.PubMedGoogle Scholar
  15. 15.
    Bacon TA, Wickstrom E. Daily addition of an anti-c-myc DNA oligomer induces granulocytic differentiation of human promyelocytic leukemia HL-60 cells in both serum-containing and serum-free media. Oncogene Research 1991; 6:21–32.PubMedGoogle Scholar
  16. 16.
    Bacon TA, Wickstrom E. Walking along human c-myc mRNA with antisense oligodeoxynucleotides: Maximum efficacy at the 5′ cap region. Oncogene Research 1991; 6:13–9.PubMedGoogle Scholar
  17. 17.
    Bartkova J, Lukas J, Muller H et al. Abnormal patterns of D-type cyclin expression and G1 regulation in human head and neck cancer. Cancer Res 1995; 55:949–56.PubMedGoogle Scholar
  18. 18.
    Baserga R. The insulin-like growth factor I receptor: A key to tumor growth? Cancer Res 1995; 55:249–52.PubMedGoogle Scholar
  19. 19.
    Basu S, Kolan HR, Thakur ML et al. Solid phase synthesis of a HYNIC-D-peptide-phosphorothioate oligodeoxynucleotide conjugate from two arms of a polyethylene glycol-polystyrene support. Journal of Labeled Compounds and Radiopharmaceuticals 1995; 37:350–352.Google Scholar
  20. 20.
    Basu S, Wickstrom E. Solid phase synthesis of a D-peptide-phosphorothioate oligodeoxynucleotide conjugate from two arms of a polyethylene glycol-polystyrene support. Tetrahedron Letters 1995; 36:4943–4946.Google Scholar
  21. 21.
    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. Bioconj Chemistry 1997; 8:481–8.CrossRefGoogle Scholar
  22. 22.
    Bayever E, Haines KM, Iversen PL et al. Selective cytotoxicity to human leukemic myeloblasts produced by oligodeoxyribonucleotide phosphorothioates complementary to p53 nucleotide sequences. Leukemia & Lymphoma 1994; 12:223–31.Google Scholar
  23. 23.
    Belikova AM, Zarytova VF, Grineva N I. Synthesis of ribonucleosides and diribonucleoside phosphates containing 2-chloroethylamine and nitrogen mustard residues. Tetrahedron Lett 1967; 37:3557–62.PubMedCrossRefGoogle Scholar
  24. 24.
    Bennett CF, Dean N, Ecker DJ et al. Pharmacology of antisense therapeutic agents. In: Agrawal S, ed. Antisense therapeutics. Totowa, NJ: Humana Press, 1996:10:13–46.CrossRefGoogle Scholar
  25. 25.
    Bertram J, Killian M, Brysch W et al. Reduction of erbB2 gene product in mamma carcinoma cell lines by erbB2 mRNA-specific and tyrosine kinase consensus phosphorothioate antisense oligonucleotides. Biochem Biophys Res Commun 1994; 200:661–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Bièche I, Laurendeau I, Tozlu S et al. Quantitation of MYC gene expression in sporadic breast tumors with a real-time reverse transcription-PCR assay. Cancer Research 1999a; 59:2759–2765.PubMedGoogle Scholar
  27. 27.
    Bièche I, Onody P, Laurendeau I et al. Real-time reverse transcription-PCR assay for future management of ERBB2-based clinical applications. Clin Chem 1999b; 45:1148–56.PubMedGoogle Scholar
  28. 28.
    Bishop JM. Molecular themes in oncogenesis. Cell 1991; 64:235–48.PubMedCrossRefGoogle Scholar
  29. 29.
    Bishop MR, Jackson JD, Tarantolo SR et al. Ex vivo treatment of bone marrow with phosphorothioate oligonucleotide OL(1)p53 for autologous transplantation in acute myelogenous leukemia and myelodysplastic syndrome. Journal of Hematotherapy 1997; 6:441–6.PubMedGoogle Scholar
  30. 30.
    Blackwood EM, Eisenman RN. Max: A helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science 1991; 251:1211–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Boffa LC, Scarfi S, Mariani MR 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
  32. 32.
    Bonham MA, Brown S, Boyd AL 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
  33. 33.
    Broaddus WC, Liu Y, Steele LL et al. Enhanced radiosensitivity of malignant glioma cells after adenoviral p53 transduction. J Neurosurg 1999; 91:997–1004.PubMedCrossRefGoogle Scholar
  34. 34.
    Brysch W, Magal E, Louis JC et al. Inhibition of p185c-erbB-2 proto-oncogene expression by antisense oligodeoxynucleotides down-regulates p185-associated tyrosine-kinase activity and strongly inhibits mammary tumor-cell proliferation. Cancer Gene Ther 1994; 1:99–105.PubMedGoogle Scholar
  35. 35.
    Cobleigh MA, Vogel CL, Tripathy NJ et al. Efficacy and safety of Herceptin (humanized anti-human HER-2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 1998; 17:97.Google Scholar
  36. 36.
    Collins JF, Herman P, Schuch C et al. c-myc antisense oligonucleotides inhibit the colony-forming capacity of Colo 320 colonic carcinoma cells. J Clin Invest 1992; 89:1523–7.PubMedGoogle Scholar
  37. 37.
    Colomer R, Lupu R, Bacus SS et al. erbB-2 antisense oligonucleotides inhibit the proliferation of breast carcinoma cells with erbB-2 oncogene amplification. Br J Cancer 1994; 70:819–25.PubMedGoogle Scholar
  38. 38.
    Daaka Y, Wickstrom E. Target dependence of antisense oligodeoxynudeotide inhibition of c-Ha-ras p21 expression and focus formation in T24-transformed NIH3T3 cells. Oncogene Research 1990; 5:267–75.PubMedGoogle Scholar
  39. 39.
    Deng C, Zhang P, Harper JW et al. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 1995; 82:675–684.PubMedCrossRefGoogle Scholar
  40. 40.
    Dong M, Nio Y, Tamura K et al. Ki-ras point mutation and p53 expression in human pancreatic cancer: A comparative study among Chinese, Japanese, and Western patients. Cancer Epidemiol Biomarkers Prev 2000; 9:279–84.PubMedGoogle Scholar
  41. 41.
    Downward J, Riehl R, Wu L et al. Identification of a nucleotide exchange-promoting activity for p21ras. Proc Natl Acad Sci USA 1990; 87:5998–6002.PubMedCrossRefGoogle Scholar
  42. 42.
    Dugan MC, Dergham ST, Kucway R et al. HER-2/neu expression in pancreatic adenocarcinoma: Relation to tumor differentiation and survival. Pancreas 1997; 14:229–36.PubMedCrossRefGoogle Scholar
  43. 43.
    Egholm M, Buchardt O, Christensen L et al. PNA hybridizes to complementary oligonucleotides obeying the Watson-Crick hydrogen-bonding rules [see comments]. Nature 1993; 365:566–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Eisenhut M, Haberkorn U. [123I]VIP receptor scintigraphy in patients with pancreatic adenocarcinomas. Eur J Nucl Med 2000; 27:1589–90.PubMedCrossRefGoogle Scholar
  45. 45.
    Gansauge S, Gansauge F, Ramadani M et al. Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res 1997; 57:1634–7.PubMedGoogle Scholar
  46. 46.
    Georges RN, Mukhopadhyay T, Zhang Y et al. Prevention of orthotopic human lung cancer growth by intratracheal instillation of a retroviral antisense K-ras construct. Cancer Res 1993; 53:1743–6.PubMedGoogle Scholar
  47. 47.
    Gibbs JB, Schaber MD, Allard WJ et al. Purification of ras GTPase activating protein from bovine brain. Proc Natl Acad Sci USA 1988; 85:5026–30.PubMedCrossRefGoogle Scholar
  48. 48.
    Goldman R, Levy RB, Peles E et al. Heterodimerization of the erbB-1 and erbB-2 receptors in human breast carcinoma cells: A mechanism for receptor transregulation. Biochemistry 1990; 29:11024–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Good L, Nielsen PE. Progress in developing PNA as a gene-targeted drug. Antisense Nucleic Acid Drug Dev 1997; 7:431–7.PubMedGoogle Scholar
  50. 50.
    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
  51. 51.
    Goodrich DW, Lee WH. Molecular characterization of the retinoblastoma susceptibility gene. Biochim. Biophys Acta 1993; 1155:43–61.Google Scholar
  52. 52.
    Gray GD, Basu S, Wickstrom E. Transformed and immortalized cellular uptake of oligodeoxynucleoside phosphorothioates, 3′-alkylamino oligodeoxynucleotides, 2′-O-methyl oligoribonucleotides, oligodeoxynucleoside methylphosphonates, and peptide nucleic acids. Biochemical Pharmacology 1997; 53:1465–76.PubMedCrossRefGoogle Scholar
  53. 53.
    Gray GD, Townsend R, Hayasaka H et al. Immune cell involvement in anti-c-myc DNA prevention of tumor formation in a mouse model of Burkitt’s lymphoma. Nucleosides and Nucleotides 1997; 16:1727–1730.Google Scholar
  54. 54.
    Gray GD, Wickstrom E. Rapid measurement of modified oligonucleotide levels in plasma samples with a fluorophore specific for single-stranded DNA. Antisense and Nucleic Acid Drug Devel 1997; 7:133–40.Google Scholar
  55. 55.
    Gurnani M, Lipari P, Dell J et al. Adenovirus-mediated p53 gene therapy has greater efficacy when combined with chemotherapy against human head and neck, ovarian, prostate, and breast cancer. Cancer Chemother Pharmacol 1999; 44:143–51.PubMedCrossRefGoogle Scholar
  56. 56.
    Hanvey JC, Peffer NJ, Bisi JE et al. Antisense and antigene properties of peptide nucleic acids. Science 1992; 258:1481–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Heikkila R, Schwab G, Wickstrom E et al. A c-myc antisense oligodeoxynucleotide inhibits entry into S phase but not progress from G0 to G1. Nature 1987; 328:445–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Helin K, Harlow E. The retinoblastoma protein as a transcriptional repressor. Trends Cell Biol 1992; 3:43–46.CrossRefGoogle Scholar
  59. 59.
    Hinds PW, Dowdy SF, Eaton EN et al. Function of a human cyclin gene as an oncogene. Proc Natl Acad Sci USA 1994; 91:709–713.PubMedCrossRefGoogle Scholar
  60. 60.
    Ho PT, Ishiguro K, Wickstrom E et al. Nonsequence-specific inhibition of transferrin receptor expression in HL-60 leukemia cells by phosphorothioate oligodeoxynucleotides. Antisense Research & Development 1991; 1:329–42.Google Scholar
  61. 61.
    Holland PM, Abramson RD, Watson R et al. Detection of specific polymerase chain reaction product by utilizing the 5′—3′ exonuclease activity of Thermus aquaticus DNA polymerase. Proc Natl Acad Sci USA 1991; 88:7276–80.PubMedCrossRefGoogle Scholar
  62. 62.
    Huang Y, Snyder R, Kligshteyn M et al. Prevention of tumor formation in a mouse model of Burkitt’s lymphoma by 6 weeks of treatment with anti-c-myc DNA phosphorothioate. Molecular Medicine 1995; 1:647–58.PubMedGoogle Scholar
  63. 63.
    Hughes J, Astriab A, Yoo H et al. In vitro transport and delivery of antisense oligonucleotides [In Process Citation]. Methods Enzymol 2000; 313:342–58.PubMedGoogle Scholar
  64. 64.
    Hustinx R, Shiue CY, Zhuang H et al. Imaging in vivo herpes simplex virus thymidine kinase gene transfer and expression in tumors using positron emission tomography. J Nucl Med 2000; 41:264P.Google Scholar
  65. 65.
    Jiang W, Kahn SM, Zhou P et al. Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression. Oncogene 1993; 8:3447–57.PubMedGoogle Scholar
  66. 66.
    Kashani-Sabet M, Funato T, Florenes VA et al. Suppression of the neoplastic phenotype in vivo by an anti-ras ribozyme. Cancer Res 1994; 54:900–2.PubMedGoogle Scholar
  67. 67.
    Kasuya K, Watanabe H, Nakasako T et al. p53 protein overexpression and K-ras codon 12 mutation in pancreatic ductal carcinoma: Correlation with histologic factors. Pathol Int 1997; 47:531–9.PubMedGoogle Scholar
  68. 68.
    Kawada M, Fukazawa H, Mizuno S et al. Inhibition of anchorage-independent growth of ras-transformed cells on polyHEMA surface by antisense oligodeoxynucleotides directed against K-ras. Biochem Biophys Res Commun 1997; 231:735–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Kennedy MM, Biddolph S, Lucas SB et al. Cyclin D1 expression and HHV8 in Kaposi sarcoma. J Clin Pathol 1999; 52:569–73.PubMedGoogle Scholar
  70. 70.
    Kita K, Saito S, Morioka CY et al. Growth inhibition of human pancreatic cancer cell lines by anti-sense oligonucleotides specific to mutated K-ras genes. Int J Cancer 1999; 80:553–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Kokai Y, Cohen JA, Drebin JA et al. Stage-and tissue-specific expression of the neu oncogene in rat development. Proc Natl Acad Sci USA 1987; 84:8498–501.PubMedCrossRefGoogle Scholar
  72. 72.
    Kraus MH, Issing W, Miki T et al. Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: Evidence for overexpression in a subset of human mammary tumors. Proc Natl Acad Sci USA 1989; 86:9193–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Krieg AM, Yi AK, Matson S et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995; 374:546–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Lal RB, Rudolph DL, Folks TM et al. Over expression of insulin-like growth factor receptor type-I in T-cell lines infected with human T-lymphotropic virus types-I and-II. Leuk Res 1993; 17:31–5.PubMedCrossRefGoogle Scholar
  75. 75.
    Leonetti C, D’Agnano I, Lozupone F et al. Antitumor effect of c-myc antisense phosphorothioate oligodeoxynucleotides on human melanoma cells in vitro and and in mice [see comments]. J Natl Cancer Inst 1996; 88:419–29.PubMedCrossRefGoogle Scholar
  76. 76.
    Liu X, Pogo BG. Inhibition of erbB-2-positive breast cancer cell growth by erbB-2 antisense oligonucleotides. Antisense Nucleic Acid Drug Dev 1996; 6:9–16.PubMedGoogle Scholar
  77. 77.
    Lovec H, Sewing A, Lucibello FC et al. Oncogenic activity of cyclin D1 revealed through cooperation with Ha-ras: Link between cell cycle control and malignant transformation. Oncogene 1994; 9:323–6.PubMedGoogle Scholar
  78. 78.
    Lowy DR, Willumsen BM. Function and regulation of ras. Annu Rev Biochem 1993; 62:851–91.PubMedCrossRefGoogle Scholar
  79. 79.
    Martin KJ, Kritzman BM, Price LM et al. Linking gene expression patterns to therapeutic groups in breast cancer [In Process Citation]. Cancer Res 60 2000; 2232–8.PubMedGoogle Scholar
  80. 80.
    Marwick C. First “antisense” drug will treat CMV retinitis [news]. JAMA 1998; 280:871.PubMedCrossRefGoogle Scholar
  81. 81.
    Matsushime HD, Quelle E, Shurtleff SA et al. D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol 1994; 14:2066–2076.PubMedGoogle Scholar
  82. 82.
    McManaway ME, Neckers LM, Loke SL et al. Tumour-specific inhibition of lymphoma growth by an antisense oligodeoxynucleotide. Lancet 1990; 335:808–11.PubMedCrossRefGoogle Scholar
  83. 83.
    Mier W, Eritja R, Mohammed A et al. Preparation and evaluation of tumor-targeting peptide-oligonucleotide conjugates. Bioconjug Chem 2000; 11:855–60.PubMedCrossRefGoogle Scholar
  84. 84.
    Mier W, Eritja R, Mohammed A et al. Preparation and predinical development of tumor-targeting peptide-PNA conjugates. J Labelled Compounds and Radiopharmaceuticals 2001; 42:115P.Google Scholar
  85. 85.
    Moberg KH, Logan TJ, Tyndall WA et al. Three distinct elements within the murine c-myc promoter are required for transcription. Oncogene 1992a; 7:411–21.PubMedGoogle Scholar
  86. 86.
    Moberg KH, Tyndall WA, Hall DJ. Wild-type murine p53 represses transcription from the murine c-myc promoter in a human glial cell line. J Cell Biochem 1992b; 49:208–15.PubMedCrossRefGoogle Scholar
  87. 87.
    Monia BP, Lesnik EA, Gonzalez C et al. Evaluation of 2′-modified oligonudeotides containing 2′-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem 1993; 268:14514–22.PubMedGoogle Scholar
  88. 88.
    Motokura T, Arnold A. PRAD1/cyclin D1 proto-oncogene: Genomic organization, 5′ DNA sequence, and sequence of a tumor-specific rearrangement breakpoint. Genes Chromosomes Cancer 1993; 7:89–95.PubMedCrossRefGoogle Scholar
  89. 89.
    Mukhopadhyay T, Tainsky M, Cavender AC et al. Specific inhibition of K-ras expression and tumorigenicity of lung cancer cells by antisense RNA. Cancer Res 1991; 51:1744–8.PubMedGoogle Scholar
  90. 90.
    Namavari M, Barrio JR, Toyokuni T et al. Synthesis of 8-[(18)F]fluoroguanine derivatives: In vivo probes for imaging gene expression with positron emission tomography. Nucl Med Biol 2000; 27:157–162.PubMedCrossRefGoogle Scholar
  91. 91.
    Nemunaitis J, Swisher SG, Timmons T et al. Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with nonsmall-cell lung cancer [In Process Citation]. J Clin Oncol 2000; 18:609.PubMedGoogle Scholar
  92. 92.
    Nevins JR. E2F; a link between the Rb tumor suppressor protein and viral oncogenesis. Science 1992; 258:424–429.PubMedCrossRefGoogle Scholar
  93. 93.
    Okada F, Rak JW, Croix BS et al. Impact of oncogenes in tumor angiogenesis: Mutant K-ras up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells. Proc Natl Acad Sci USA 1998; 95:3609–14.PubMedCrossRefGoogle Scholar
  94. 94.
    Oliff A. Farnesyltransferase inhibitors: Targeting the molecular basis of cancer. Biochim Biophys Acta 1999; 1423:C19–30.PubMedGoogle Scholar
  95. 95.
    Pallela VR, Thakur ML, Chakder S. 99mTc-labeled vasoactive intestinal peptide receptor agonist: Functional studies. J Nucl Med 1999; 40:352–60.PubMedGoogle Scholar
  96. 96.
    Pallela VR, Thakur ML, Consigny PM et al. Imaging thromboembolism with Tc-99m-labeled thrombospondin receptor analogs TP-1201 and TP-1300. Thromb Res 1999; 93:191–202.PubMedCrossRefGoogle Scholar
  97. 97.
    Pietrzkowski Z, Sell C, Lammers R et al. Roles of insulinlike growth factor 1 (IGF-1) and the IGF-1 receptor in epidermal growth factor-stimulated growth of 3T3 cells. Mol Cell Biol 1992; 12:3883–9.PubMedGoogle Scholar
  98. 98.
    Pietrzkowski Z, Wernicke D, Porcu P et al. Inhibition of cellular proliferation by peptide analogues of insulin-like growth factor 1. Cancer Res 1992; 52:6447–51.PubMedGoogle Scholar
  99. 99.
    Pirollo KF, Hao Z, Rait A et al. Evidence supporting a signal transduction pathway leading to the radiation-resistant phenotype in human tumor cells. Biochem Biophys Res Commun 1997;230:196–201.PubMedCrossRefGoogle Scholar
  100. 100.
    Ponomarev V, Dubrovin M, Balatoni J et al. PET imaging of p53 gene expression in tumors. J Nucl Med 2000; 41:263P–264P.Google Scholar
  101. 101.
    Press MF, Pike MC, Chazin VR et al. Her-2/neu expression in node-negative breast cancer: Direct tissue quantitation by computerized image analysis and association of overexpression with increased risk of recurrent disease. Cancer Res 1993; 53:4960–70.PubMedGoogle Scholar
  102. 102.
    Qiao Q, Ramadani M, Gansauge S et al. Reduced membranous and ectopic cytoplasmic expression of beta-catenin correlate with cyclin D1 overexpression and poor prognosis in pancreatic cancer. Int J Cancer 2001; 95:194–7.PubMedCrossRefGoogle Scholar
  103. 103.
    Quelle DE, Ashmun RA, Shurtleff SA et al. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev 1993; 7:1559–71.PubMedGoogle Scholar
  104. 104.
    Rait VK, Shaw BR. Boranophosphates support the RNase H cleavage of polyribonucleotides. Antisense Nucleic Acid Drug Dev 1999; 9:53–60.PubMedGoogle Scholar
  105. 105.
    Reubi JC. Neuropeptide receptors in health and disease: The molecular basis for in vivo imaging [see comments]. J Nucl Med 1995; 36:1825–35.PubMedGoogle Scholar
  106. 106.
    Robinson LA, Smith LJ, Fontaine MP et al. c-myc antisense oligodeoxyribonucleotides inhibit proliferation of non small cell lung cancer. Ann Thorac Surg 1995; 60:1583–91.PubMedCrossRefGoogle Scholar
  107. 107.
    Ross JS, Fletcher JA. The HER-2/neu Oncogene in Breast Cancer: Prognostic Factor, Predictive Factor, and Target for Therapy. Oncologist 1998; 3:237–252.PubMedGoogle Scholar
  108. 108.
    Ru K, Taub ML, Wang JH. Specific inhibition of breast cancer cells by antisense poly-DNP-oligoribonucleotides and targeted apoptosis. Oncol Res 1998; 10:389–97.PubMedGoogle Scholar
  109. 109.
    Sauter ER, Cleveland D, Trock B et al. p53 is overexpressed in fifty percent of preinvasive lesions of head and neck epithelium. Carcinogenesis 1994; 15:2269–74.PubMedCrossRefGoogle Scholar
  110. 110.
    Sauter ER, Herlyn M, Liu SC et al. Prolonged response to antisense cyclin D1 in a human squamous cancer xenograft model. Clin Cancer Res 2000; 6:654–60.PubMedGoogle Scholar
  111. 111.
    Sauter ER, Keller SM, Erner S et al. HER-2/neu: A differentiation marker in adenocarcinoma of the esophagus. Cancer Lett 1993; 75:41–4.PubMedCrossRefGoogle Scholar
  112. 112.
    Sauter ER, Nesbit M, Litwin S et al. Antisense cyclin D1 induces apoptosis and tumor shrinkage in human squamous carcinomas [In Process Citation]. Cancer Res 1999a; 59:4876–81.PubMedGoogle Scholar
  113. 113.
    Sauter ER, Nesbit M, Litwin S et al. Combination gene therapy to treat human malignant melanoma. Proc Am Assoc Cancer Res 1999b; 40:3951A.Google Scholar
  114. 114.
    Sauter ER, Ridge JA, Litwin S et al. Pretreatment p53 protein expression correlates with decreased survival in patients with end-stage head and neck cancer. Clin Cancer Res 1995a; 1:1407–12.PubMedGoogle Scholar
  115. 115.
    Sauter ER, Ridge JA, Trock B et al. Overexpression of the p53 gene in primary and metastatic head and neck carcinomas. Laryngoscope 1995b; 105:653–6.PubMedCrossRefGoogle Scholar
  116. 116.
    Schechter AL, Hung MC, Vaidyanathan L et al. The neu gene: An erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. Science 1985; 229:976–8.PubMedCrossRefGoogle Scholar
  117. 117.
    Seidman AD. Single-agent paclitaxel in the treatment of breast cancer: Phase I and II development. Semin Oncol 1999; 26:14–20.PubMedGoogle Scholar
  118. 118.
    Shaw BR, Sergueev D, He K et al. Boranophosphate backbone: A mimic of phosphodiesters, phosphorothioates, and methyl phosphonates. Methods Enzymol 2000; 313:226–57.PubMedCrossRefGoogle Scholar
  119. 119.
    Slamon D, Leyland-Jones B, Shak S et al. Addition of Herceptin (humanized anti-human HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic brest cancer markedly increases anticancer activity: A randomized, multinational controlled phase III trial. Proc Am Soc Clin Oncol 1998; 17:98.Google Scholar
  120. 120.
    Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235:177–82.PubMedCrossRefGoogle Scholar
  121. 121.
    Smith JB, Wickstrom E. Antisense c-myc and immunostimulatory oligonucleotide inhibition of tumorigenesis in a murine B-cell lymphoma transplant model. J Natl Cancer Inst 1998; 90:1146–54.PubMedCrossRefGoogle Scholar
  122. 122.
    Smith JB, Wickstrom E. Preclinical antisense DNA therapy of cancer in mice. Methods Enzymol 2000; 314:537–80.PubMedGoogle Scholar
  123. 123.
    St John LS, Sauter ER, Herlyn M et al. Endogeneous p53 gene status predicts response of human squamous cell carcinomas to wild-type p53. Cancer Gene Therapy, 2000; 7:749–56.PubMedCrossRefGoogle Scholar
  124. 124.
    Stalteri MA, Mather SJ. Hybridization and cell uptake studies with radiolabelled antisense oligonucleotides. Nucl Med Commun 2001; 22:1171–9.PubMedCrossRefGoogle Scholar
  125. 125.
    Tada M, Omata M, Kawai S et al. Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res 1993; 53:2472–4.PubMedGoogle Scholar
  126. 126.
    Tan MH, Chu TM. Characterization of the tumorigenic and metastatic properties of a human pancreatic tumor cell line (AsPC-1) implanted orthotopically into nude mice. Tumour Biol 1985; 6:89–98.PubMedGoogle Scholar
  127. 127.
    Tan TM, Kalisch BW, van de Sande JH et al. Biologic activity of oligonucleotides with polarity and anomeric center reversal. Antisense Nucleic Acid Drug Dev 1998; 8:95–101.PubMedGoogle Scholar
  128. 128.
    Thakur ML, Marcus CS, Saeed S et al. 99mTc-labeled vasoactive intestinal peptide analog for rapid localization of tumors in humans. J Nucl Med 2000; 41:107–10.PubMedGoogle Scholar
  129. 129.
    Thakur ML, Pallela VR, Consigny PM et al. Imaging vascular thrombosis with 99mTc-labeled fibrin alpha-chain peptide. J Nucl Med 2000; 41:161–8.PubMedGoogle Scholar
  130. 130.
    Thissen JA, Gross JM, Subramanian K et al. Prenylation-dependent association of Ki-Ras with microtubules. Evidence for a role in subcellular trafficking. J Biol Chem 1997; 272:30362–70.PubMedCrossRefGoogle Scholar
  131. 131.
    Thor AD, Berry DA, Budman DR et al. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer [see comments]. J Natl Cancer Inst 1998; 90:1346–60.PubMedCrossRefGoogle Scholar
  132. 132.
    Thor AD, Moore DH, II Edgerton SM et al. Accumulation of p53 tumor suppressor gene protein: An independent marker of prognosis in breast cancers. J Natl Cancer Inst 1992; 84:845–55.PubMedCrossRefGoogle Scholar
  133. 133.
    Tong Z, Singh G, Rainbow AJ. The role of the p53 tumor suppressor in the response of human cells to photofrin-mediated photodynamic therapy [In Process Citation]. Photochem Photobiol 2000; 71:201–10.PubMedCrossRefGoogle Scholar
  134. 134.
    Ullrich A, Gray A, Tam AW et al. Insulin-like growth factor I receptor primary structure: Comparison with insulin receptor suggests structural determinants that define functional specificity. Embo J 1986; 5:2503–12.PubMedGoogle Scholar
  135. 135.
    Ulsh LS, Shih TY. Metabolic turnover of human c-rasH p21 protein of EJ bladder carcinoma and its normal cellular and viral homologs. Mol Cell Biol 1984; 4:1647–52.PubMedGoogle Scholar
  136. 136.
    Vaughn JP, Iglehart JD, Demirdji S et al. Antisense DNA downregulation of the ERBB2 oncogene measured by a flow cytometric assay. Proc Natl Acad Sci USA 1995; 92:8338–42.PubMedCrossRefGoogle Scholar
  137. 137.
    Vaughn JP, Stekler J, Demirdji S et al. Inhibition of the erbB-2 tyrosine kinase receptor in breast cancer cells by phosphoromonothioate and phosphorodithioate antisense oligonucleotides. Nucleic Acids Res 1996; 24:4558–64.PubMedCrossRefGoogle Scholar
  138. 138.
    Walder RY, Walder JA. Role of RNase H in hybrid-arrested translation by antisense oligonucleotides. Proc Natl Acad Sci USA 1988; 85:5011–5.PubMedCrossRefGoogle Scholar
  139. 139.
    Watson PH, Pon RT, Shiu RP. Inhibition of c-myc expression by phosphorothioate antisense oligonucleotide identifies a critical role for c-myc in the growth of human breast cancer. Cancer Res 1991; 51:3996–4000.PubMedGoogle Scholar
  140. 140.
    Wickstrom E. Prospects for Antisense Nucleic Acid Therapy of Cancer and AIDS, New York: Wiley-Liss, 1991.Google Scholar
  141. 141.
    Wickstrom E. Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, New York: Marcel Dekker, 1998.Google Scholar
  142. 142.
    Wickstrom E, Bacon TA, Wickstrom EL. Down-regulation of c-MYC antigen expression in lymphocytes of Eμ-c-myc transgenic mice treated with anti-c-myc DNA methylphosphonates. Cancer Research 1992; 52:6741–5.PubMedGoogle Scholar
  143. 143.
    Wickstrom E, Simonet WS, Medlock K et al. Complementary oligonucleotide probe of vesicular stomatitis virus matrix protein mRNA secondary structure. Biophysical Journal 1986; 49:15–17.CrossRefPubMedGoogle Scholar
  144. 144.
    Wickstrom E, Tyson FL. Differential oligonucleotide activity in cell culture versus mouse models. Ciba Found Symp 1997; 209:124–37; discussion 137—41.PubMedGoogle Scholar
  145. 145.
    Wickstrom EL, Bacon TA, Gonzalez A et al. Human promyelocytic leukemia HL-60 cell proliferation and c-myc protein expression are inhibited by an antisense pentadecadeoxynucleotide targeted against c-myc mRNA. Proc Natl Acad Sci USA 1988; 85:1028–32.PubMedCrossRefGoogle Scholar
  146. 146.
    Wickstrom EL, Bacon TA, Gonzalez A et al. Anti-c-myc DNA increases differentiation and decreases colony formation by HL-60 cells. In Vitro Cellular & Developmental Biology 1989; 25:297–302.Google Scholar
  147. 147.
    Wickstrom EL, Wickstrom E, Lyman GH et al. HL60 cell proliferation inhibited by an anti-c-myc pentadecadeoxynucleotide. Fed Proc 1986; 45:1708.Google Scholar
  148. 148.
    Xu L, Pirollo KF, Tang WH et al. Transferrin-liposome-mediated systemic p53 gene therapy in combination with radiation results in regression of human head and neck cancer xenografts. Hum Gene Ther 1999; 10:2941–52.PubMedCrossRefGoogle Scholar
  149. 149.
    Yamaguchi K, Chijiiwa K, Noshiro H et al. Ki-ras codon 12 point mutation and p53 mutation in pancreatic diseases. Hepatogastroenterology 1999; 46:2575–81.PubMedGoogle Scholar
  150. 150.
    Yasuda D, Iguchi H, Ikeda Y et al. Possible association of nm23 gene expression and Ki-ras point mutations with metastatic potential in human pancreatic cancer-derived cell lines. Int J Oncol 1993; 3:641–4.Google Scholar
  151. 151.
    Zamecnik PC, Stephenson ML Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci USA 1978; 75:280–4.PubMedCrossRefGoogle Scholar
  152. 152.
    Zhang Y, Yu D, Xia W et al. HER-2/neu-targeting cancer therapy via adenovirus-mediated E1A delivery in an animal model. Oncogene 1995; 10:1947–54.PubMedGoogle Scholar

Copyright information

© and Kluwer Academic / Plenum Publishers 2006

Authors and Affiliations

  • Eric Wickstrom
    • 1
  • Mathew L. Thakur
    • 2
  • Edward R. Sauter
    • 3
  1. 1.Department of Biochemistry and Molecular Biology Department of Microbiology and Immunology Kimmel Cancer Center Cardeza Foundation for Hematologic Research Jefferson Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Department of Radiology Kimmel Cancer Center Jefferson Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA
  3. 3.Department of Surgery Ellis Fischel Cancer CenterUniversity of MissouriColumbiaUSA

Personalised recommendations