Antisense DNAs as Targeted Genetic Medicine to Treat Cancer

  • Chochung, Yoo-S. (Cellular Biochemistry Section, Basic Research Laboratory, National Cancer Institute)
  • Published : 2003.03.01

Abstract

Nucleic acid therapies represent a direct genetic approach for cancer treatment. Such an approach takes advantage of mechanisms that activate genes known to confer a growth advantage to neoplastic cells. The ability to block the expression of these genes allows exploration of normal growth regulation. Progress in antisense technology has been rapid, and the traditional antisense inhibition of gene expression is now viewed on a genomic scale. This global view has led to a new vision in antisense technology, the elimination of nonspecific and undesirable side effects, and ultimately, the generation of more effective and less toxic nucleic acid medicines. Several antisense oligonucleotides are in clinical trials, are well tolerated, and are potentially active therapeutically. Antisense oligonucleotides are promising molecular medicines for treating human cancer in the near future.

Keywords

References

  1. Agrawal, S., Antisense oligonucleotides: towards clinical trials. Trends Biotechnol., 14, 376-387 (1996a) https://doi.org/10.1016/0167-7799(96)10053-6
  2. Agrawal, S., Antisense therapeutics. New Jersey, Humana Press (1996b)
  3. Agrawal, S., Jiang, Z., Zhao, Q., Shaw, D., Cai, Q., Roskey, A., Channavajjala, L., Saxinger, C., and Zhang, R., Mixed-backbone oligonucleotides as second generation antisense oligonucleotides: in vitro and in vivo studies. Proc. Natl. Acad. Sci. USA, 94, 2620 (1997) https://doi.org/10.1073/pnas.94.6.2620
  4. Agrawal, S. and Zhao, Q., Mixed backbone oligonucleotdes: improvement in oligonucleotide-induced toxicity in vivo. Antisense & Nucleic Acid Drug Dev., 8, 135-139 (1998a) https://doi.org/10.1089/oli.1.1998.8.135
  5. Agrawal, S. and Zhao, Q., Antisense therapeutics. Curr. Opin. Chem. Biol., 2, 519-528 (1998b) https://doi.org/10.1016/S1367-5931(98)80129-4
  6. Akhtar, S. and Agrawal, S., In vivo studies with antisense oligonucleotides. Trends Pharmacol Sci., 18, 12-18 (1997) https://doi.org/10.1016/S0165-6147(96)01002-4
  7. Alizadeh, A. A., Eisen, M. B., Davis, R. E., Ma, C., Lossos, I. S., Rosenwald, A., Boldrick, J. C., Sabet, H., Tran, T., Yu, X., Powell, J. I., Yang, L., Marti, G. E., Moore, T., Hudson, J., Lu, Jr., L., Lewis, D. B., Tibshirani, R., Sherlock, G., Chan, W. C., Greiner, T.C., Weisenburger, D. D., Armitage, J. O., Warnke, R., Staudt, L. M., Levy, R., Wilson, W., Grevor, M. R., Byrd, J. C., Botstein, D., and Brown, P. O., Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature, 403, 503-511 (2000)/ࠀ患⨀儀덀倀Ѐꠏ?⨀Ā쀒렄⨀Ѐं덐蠒?⨀蠏?⨀䀀Ȁ衕잖⨀뀛?⨀섂돀烫?⨀塨?⨀联잖⨀怂⨀餂덐ꢎ⨀頂堕?⨀联잖⨀ЀЀ܀退㄀푄ሄ怕?⨀뢣⨀䤀礀䀐䲜Ā䀀ሀĀࠀࢤ憭憭¥憭₥憭ᢣ徨塓ꂛ쁶잖⨀ᨀ笀㪬Ā䀀ሀĀ਀뀽ᄊ?ᄊᄊᄊ颷㒰낷㒰졷잖⨀଀礀존뚓 https://doi.org/10.1038/35000501
  8. Alper, O., Hacker, N. F., and Cho-Chung, Y. S., Protein kinase A RI$\alpha$ subunit-directed antisense inhibition of ovarian cancer cell growth: crosstalk with tyrosine kinase signaling pathway. Oncogene, 18, 4999-5004 (1999) https://doi.org/10.1038/sj.onc.1202830
  9. Amieux, P. S., Cummings, D. E., Motamed, K., Brandon, E. P., Wailes, L. A., Le, K., Idzerda, R. L., and McKnight, G. S., Compensatory regulation of RIalpha protein levels in protein kinase A mutant mice. J. Biol. Chem., 272, 3993-3998 (1997) https://doi.org/10.1074/jbc.272.7.3993
  10. Bennett, C. F., Antisense oligonucleotides: is the glass half full or half empty? Biochem. Pharmacol., 55, 9-19 (1998) https://doi.org/10.1016/S0006-2952(97)00214-1
  11. Bold, R. J., Alpard, S., Ishizuka, J., Townsend, Jr. C. M., and Thompson, J. C., Growth-regulatory effect of gastrin on human colon cancer cell lines is determined by protein kinase a isoform content. Regul. Pept., 53, 61-70 (1994) https://doi.org/10.1016/0167-0115(94)90159-7
  12. Bradbury, A. W., Carter, D. C., Miller, W. R., Cho-Chung, Y. S., and Clair, T., Protein kinase A (PK-A) regulatory subunit epxression in colorectal cancer and related mucosa. Br. J. Cancer, 69, 738-742 (1994) https://doi.org/10.1038/bjc.1994.139
  13. Buolamwini, J. K., Novel anticancer drug discovery. Curr. Opin. Chem. Biol., 3, 500-509 (1999) https://doi.org/10.1016/S1367-5931(99)80073-8
  14. Calabretta, B. and Skorski, T., Targeting c-myc in leukemia. Anticancer Drug Des., 12, 373-381 (1997)
  15. Chen, H. X., Marshall, J. L., Ness, E., Martin, R. R., Dvorchik, B., Rizvi, N., Marquis, I., McKinlay, M., Dahut, W., and Hawkins, M. J., A safety and pharmacokinetic study of a mixed-backbone oligonucleotide (GEM 231) targeting the type I protein kinase A by 2-hour infusions in patients with refractory solid tumors. Clin. Cancer. Res., 6, 1259-1266 (2000)
  16. Chen, L., Agrawal, S., Zhou, W., Zhang, R., and Chen, J., Synergistic activation of p53 by inhibition of MDM2 expression and DNA damage. Proc. Natl. Acad. Sci. USA, 95, 195-200 (1998) https://doi.org/10.1073/pnas.95.1.195
  17. Chi, K. N., Gleave, M. E., Klasa, R., Murray, N., Bryce, C., Lopes de Menezes, D. E., D'Aloisio, S., and Tolcher, A. W., A phase I dose-finding study of combined treatment with an antisense Bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormone-refractory prostate cancer. Clin. Cancer. Res., 7, 3920-3927 (2001)
  18. Cho, Y. S., Kim, M.-K., Cheadle, C., Neary, C., Becker, K. G., and Cho-Chung, Y. S., Antisense DNAs as multisite genomic modulators identified by DNA microarray. Proc. Natl. Acad. Sci. USA, 98, 9819-9823 (2001) https://doi.org/10.1073/pnas.171314398
  19. Cho, Y. S., Kim, M. K., Tan, L., Srivastava, R., Agrawal, S., and Cho-Chung, Y. S., Protein kinase A RI$\alpha$ antisense inhibition of PC3M prostate cancer cell growth: Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad- hypophosphorylation. Clin. Cancer. Res., 8, 607-614 (2002)
  20. Cho-Chung, Y. S., Antisense and therapeutic oligonucleotides: toward a gene-targeting cancer clinic. Exp. Opin. Ther. Patent., 10, 1711-1724 (2000) https://doi.org/10.1517/13543776.10.11.1711
  21. Cho-Chung, Y. S., Antisense DNAs as targeted therapeutics for cancer: No longer a dream. Curr. Opin. Invest. Drugs, 3, 934-939 (2002)
  22. Cho-Chung, Y. S., Clair, T., Tagliaferri, P., Ally, S., Katsaros, D., Tortora, G., Neckers, L., Avery, T. L., Crabtree, G. W., and Robins, R. K., Site-selective cyclic AMP analogs as new biological tools in growth control, differentiation and protooncogene regulation. Cancer Inv., 7, 161-177 (1989) https://doi.org/10.3109/07357908909038282
  23. Cho-Chung, Y. S., Clair, T., Tortora, G., and Yokozaki, H., Role of site-selective cAMP analogs in the control and reversal of malignancy. Pharmac. Ther., 50, 1-33 (1991) https://doi.org/10.1016/0163-7258(91)90071-S
  24. Cho-Chung, Y. S., Nesterova, M., Pepe, S., Lee, G. R., Noguchi, K., Srivastava, R. K., Srivastava, A. R., Alper, O., Park, Y. G., and Lee, Y. N., Antisense DNA-targeting protein kinase ARI a subunit: a novel approach to cancer treatment. Front. Biosci., 4, D898-907 (1999) https://doi.org/10.2741/Cho-Chung
  25. Ciardiello, F., Pepe, S., Bianco, C., Baldassarre, G., Ruggiero, A., Selvam, M. P., Bianco, A. R., and Tortora, G., Downregulation of RIa subunit of cAMP-dependent protein kinase induces growth inhibition of human mammary epithelial cells transformed by c-Ha-ras and c-erbB-2 proto-oncogenes. Int. J. Cancer, 53, 438-443 (1993) https://doi.org/10.1002/ijc.2910530315
  26. Citro, G., D'Agnano, I., Leonetti, C., Perini, R., Bucci, B., Zon, G., Calabretta, B., and Zupi, G., c-myc antisense oligodeoxynucleotides enhance the efficacy of cisplatin in melanoma chemotherapy in vitro and in nude mice. Cancer Res., 58, 283-289 (1998)
  27. Cowsert, L. M., In vitro and in vivo activity of antisense inhibitors of ras: potential for clinical development. Anticancer Drug Des., 12, 359-371 (1997)
  28. Crooke, S., Antisense Research and Application. New York, Springer (1998)
  29. Dorr, F., Antisense Oligonucleotides in the Treatment of Cancer. Antisense Nucleic. Acid. Drug Dev., 9, 391-396 (1999)
  30. Dove, A., Antisense and sensibility. Nat. Biotechnol., 20, 121-124 (2002) https://doi.org/10.1038/nbt0202-121
  31. Fennewald, S. M. and Rando, R. F., Inhibition of high affinity basic fibroblast growth factor binding by oligonucleotides. J. Biol. Chem., 270, 21718-21721 (1995) https://doi.org/10.1074/jbc.270.37.21718
  32. Geiger, T., Muller, M., Dean, N.M., and Fabbro, D., Antitumor activity of a PKC-$\alpha$ antisense oligonucleotide in combination with standard chemotherapeutic agents against various human tumors transplanted into nude mice. Anticancer Drug Des., 13, 35-45 (1998)
  33. Gewirtz, A. M., Antisense oligonucleotide therapeutics for human leukemia. Curr. Opin. Hematol., 5, 59-71 (1998) https://doi.org/10.1097/00062752-199801000-00011
  34. Gewirtz, A. M., Oligonucleotide therapeutics: a step forward. J. Clin. Oncol., 18, 1809-1811 (2000) https://doi.org/10.1200/JCO.2000.18.9.1809
  35. Gordge, P. C., Hulme, M. J., Clegg, R. A., and Miller, W. R., Elevation of protein kinase A and protein kinase C activities in malignant as compared with normal human breast tissue. Eur. J. Cancer, 32A, 2120-2126 (1996)
  36. Guvakova, M. A., Yakubov, L. A., Vlodavsky, I., Tonkinson, J. L., and Stein, C. A., Phosphorothioate oligodeoxynucleotides bind to basic fibroblast growth factor, inhibit its binding to cell surface receptors, and remove it from low affinity binding sites on extracellular matrix. J. Biol. Chem., 270, 2620-2627 (1995) https://doi.org/10.1074/jbc.270.6.2620
  37. Handschin, J. S. and Eppenberger, U., Altered cellular ratio of type I and type II cyclic AMP-dependent protein kinase in human mammary tumors. FEBS Lett., 106, 301-304 (1979) https://doi.org/10.1016/0014-5793(79)80519-0
  38. Harada, H., Becknell, B., Wilm, M., Huang, L. J., Taylor, S. S., Scott, J. D., and Korsmeyer, S. J., Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol. Cell., 3, 413-422 (1999) https://doi.org/10.1016/S1097-2765(00)80469-4
  39. Hendrzak, J. A. and Brunda, M. J., Interleukin-12. Biologic activity, therapeutic utility, and role in disease. Lab. Invest., 72, 619-637 (1995)
  40. Jansen, B., Wacheck, V., Heere-Ress, E., Schlagbauer-Wadl, H., Hoeller, C., Lucas, T., Hoermann, M., Hollenstein, U., Wolff, K., and Pehamberger, H., Chemosensitisation of malignant melanoma by Bcl-2 antisense therapy. Lancet., 356, 1728-1733 (2000) https://doi.org/10.1016/S0140-6736(00)03207-4
  41. Klasa, R. J., Gillum, A. M., Klem, R. E., and Frankel, S. R., Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic. Acid. Drug Dev., 12, 193-213 (2002) https://doi.org/10.1089/108729002760220798
  42. Klinman, D. M., Yi, A. K., Beaucage, S. L., Conover, J., and Krieg, A. M., CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. Proc. Natl. Acad. Sci. USA, 93, 2879-2883 (1996) https://doi.org/10.1073/pnas.93.7.2879
  43. Krebs, E. G., Protein kinases. Curr. Top. Cell. Regul., 5, 99-133 (1972)
  44. Krieg, A. M., Leukocyte stimulation by oligodeoxynucleotides, In C. A. Stein and A. M. Krieg, Eds. Applied Antisense Oligonucleotide Technology. New York, Wiley-Liss, pp. 431-448 (1998)
  45. Krieg, A. M., Yi, A. K., Matson, S., Waldschmidt, T. J., Bishop, G. A., Teasdale, R., Koretzky, G. A., and Klinman, D. M., CpG motifs in bacterial DNA trigger direct B-cell activation. Nature, 374, 546-549 (1995) https://doi.org/10.1038/374546a0
  46. Luger, S. M., O'Brien, S. G., Ratajczak, J., Ratajczak, M. Z., Mick, R., Stadtmauer, E. A., Nowell, P. C., Goldman, J. M., and Gewirtz, A. M., Oligodeoxynucleotide-mediated inhibition of c-myb gene expression in autografted bone marrow: a pilot study. Blood., 99, 1150-1158 (2002) https://doi.org/10.1182/blood.V99.4.1150
  47. McDaid, H. M., Cairns, M. T., Atkinson, R. I., McAleer, S., Harkin, D. P., Gilmore, P., and Johnston, P. G., Increased expression of the RI$\alpha$ subunit of the cAMP-dependent protein kinase A is associated with advanced stage of ovarian cancer. Br. J. Cancer., 79, 933-939 (1999) https://doi.org/10.1038/sj.bjc.6690149
  48. Metelev, V., Liszlewicz, J., and Agrawal, S., Study of antisense oligonucleotide phosphorothioates containing segments of oligodeoxynucleotides and 2'-O-methyloligoribonucleotides. Bioorg. Medicinal Chem. Lett., 4, 2929-2934 (1994) https://doi.org/10.1016/S0960-894X(01)80842-8
  49. Miller, W. R., Hulme, M. J., Cho-Chung, Y. S., and Elton, R. A., Types of cyclic AMP binding proteins in human breast cancers. Eur. J. Cancer, 29A, 989-991 (1993a)
  50. Miller, W. R., Watson, D. M. A., Jack, W., Chetty, U., and Elton, R. A., Tumor cyclic AMP binding proteins: An independent prognostic factor for disease recurrence and survival in breast cancer. Breast. Cancer. Res. Treat., 26, 89-94 (1993b) https://doi.org/10.1007/BF00682703
  51. Monia, B. P., First- and second-generation antisense inhibitors targeted to human c- raf kinase: in vitro and in vivo studies. Anticancer Drug Des., 12, 327-339 (1997)
  52. Monia, B. P., Lesnik, E. A., Gonzalez, C., Lima, W. F., McGee, D., Guinosso, C. J., Kawasaki, A. M., Cook, P. D., and Freier, S. M., Evaluation of 2'-modified oligonucleotides containing 2'-deoxygaps as antisense inhibitors of gene expression. J. Biol. Chem., 268, 14514-14522 (1993)
  53. Nesterova, M. and Cho-Chung, Y. S., A single-injection protein kinase A-directed antisense treatment to inhibit humor growth. Nat. Med., 1, 528-633 (1995) https://doi.org/10.1038/nm0695-528
  54. Nesterova, M. and Cho-Chung, Y. S., Oligonucleotide sequencespecific inhibition of gene expression, tumor growth inhibition, and modulation of cAMP signaling by an RNA-DNA hybrid antisense targeted to protein kinase A RI$\alpha$ subunit. Antisense & Nucleic Acid Drug Development, 10, 423-433 (2000) https://doi.org/10.1089/oli.1.2000.10.423
  55. Nesterova, M., Noguchi, K., Park, Y. G., Lee, Y. N., and Cho- Chung, Y. S., Compensatory stabilization of RII$\beta$ protein, cell cycle deregulation, and growth arrest in colon and prostate carcinoma cells by antisense-directed down-regulation of protein kinase A RI$\alpha$ protein. Clinical. Cancer. Research, 6, 3434-3441 (2000)
  56. Nesterova, M. V., Yokozaki, H., McDuffie, L., and Cho-Chung, Y. S., Overexpression of RII regulatory subunit of protein kinase A in human colon carcinoma cell induces growth arrest and phenotypic changes that are abolished by site-directed mutation of RII$\beta$. Eur. J. Biochem., 235, 486-494 (1996) https://doi.org/10.1111/j.1432-1033.1996.00486.x
  57. Paterson, B. M., Roberts, B. E., and Kuff, E. L., Structural gene identification and mapping by DNA-mRNA hybrid-arrested cell-free translation. Proc. Natl. Acad. Sci. USA, 74, 4370-4374 (1977) https://doi.org/10.1073/pnas.74.10.4370
  58. Pisetsky, D. S., Immune activation by bacterial DNA: a new genetic code. Immunity, 5, 303-310 (1996) https://doi.org/10.1016/S1074-7613(00)80256-3
  59. Schena, M., Shalon, D., Davis, R. W., and Brown, P. O., Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science, 270, 467-470 (1995) https://doi.org/10.1126/science.270.5235.467
  60. Sharma, H., Hsiao, W. R., and Narayanan, R., Telomerase as a potential molecular target to study G-quartet phosphorothioates. Antisense Nucleic. Acid Drug Dev., 6, 3-7 (1996) https://doi.org/10.1089/oli.1.1996.6.3
  61. Shibahara, S., Mukai, S., Morisawa, H., Nakashima, H., Kobayashi, S., and Yamamoto, N., Inhibition of human immunodeficiency virus (HIV-1) replication by synthetic oligo-RNA derivatives. Nucleic Acids. Res., 17, 239-252 https://doi.org/10.1093/nar/17.1.239
  62. Simpson, B. J. B., Ramage, A. D., Hulme, M. J., Burns, D. J., Katsaros, D., Langdon, S. P., and Miller, W. R., Cyclic adenosine 3',5'-monophosphate-binding proteins in human ovarian cancer: Correlations with clinicapachological features. Clin. Cancer Res., 2, 201-206 (1996)
  63. Srivastava, R. K., Srivastava, A. R., Korsmeyer, S. J., Nesterova, M., Cho-Chung, Y. S., and Longo, D. L., Involvement of microtubules in the regulation of Bcl2 phosphorylation and apoptosis through cyclic AMP-dependent protein kinase. Mol. Cell Biol., 18,3509-3517 (1998a) https://doi.org/10.1128/MCB.18.6.3509
  64. Srivastava, R. K., Srivastava, A. R., Park, Y. G., Agrawal, S., and Cho-Chung, Y., Antisense depletion of R1-alpha subunit of protein kinase A induces apoptosis and growth arrest in human breast cancer cells, Breast Cancer Res. Treat., 49, 97 (1998b) https://doi.org/10.1023/A:1005905723550
  65. Srivastava, R. K., Srivastava, A. R., Seth, P., Agrawal, S., and Cho-Chung, Y. S., Growth arrest and induction of apoptosis in breast cancer cells by antisense depletion of protein kinase A-RI alpha subunit: p53-independent mechanism of action. Mol. Cell Biochem., 195, 25-36 (1999) https://doi.org/10.1023/A:1006990231186
  66. Stein, C. and Cheng, Y.-A., Antisense inhibition of gene expression, In V. DeVita, S. Rosenberg and S. Hellman, Eds. Principles and Practice of Oncology. New York, Lippincott, pp. 3059-3074 (1997)
  67. Stein, C. and Krieg, A., Applied Antisense Oligonucleotide Technology. New York, NY, Wiley-Liss, Inc. (1998)
  68. Steinberg, R. A. and Agard, D. A., Turnover of regulatory subunit of cyclic AMP-dependent protein kinase in S49 mouse lymphoma cells. Regulation by catalytic subunit and analogs of cyclic AMP. J. Biol. Chem., 256, 10731-10734 (1981)
  69. Strieter, R. M., Standiford, T. J., Huffnagle, G. B., Colletti, L. M., Lukacs, N. W., and Kunkel, S. L., “The good, the bad, and the ugly.” The role of chemokines in models of human disease. J. Immunol., 156, 3583-3586 (1996)
  70. Tamm, I., Dorken, B., and Hartmann, G., Antisense therapy in oncology: new hope for an old idea? Lancet., 358, 489-497 (2001) https://doi.org/10.1016/S0140-6736(01)05629-X
  71. Tortora, G., Bianco, R., Damiano, V., Fontanini, G., De Placido, S., Bianco, A. R., and Ciardiello, F., Oral antisense that targets protein kinase A cooperates with taxol and inhibits tumor growth, angiogenesis, and growth factor production. Clin. Cancer Res., 6, 2506-2512 (2000)
  72. Tortora, G., Caputo, R., Damiano, V., Bianco, R., Fontanini, G., Cuccato, S., De Placido, S., Bianco, A. R., and Ciardiello, F., Combined blockade of protein kinase A and bcl-2 by antisense strategy induces apoptosis and inhibits tumor growth and angiogenesis. Clin. Cancer Res., 7, 2537-2544 (2001)
  73. Tortora, G., Caputo, R., Damiano, V., Bioance, R., Peppe, S., and et al., Synergistic inhibition of human cancer cell growth by cytotoxic drugs and mixed backbone antisense oligonucleotides targeting protein kinase A. Proc. Natl. Acad. Sci. USA, 94, 12586-12591 (1997) https://doi.org/10.1073/pnas.94.23.12586
  74. Tortora, G., Ciardiello, F., Ally, S., Clair, T., Salomon, D. S., and Cho-Chung, Y. S., Site-selective 8-chloroadenosine 3',5'-cyclic monophosphate inhibits transformation and transforming growth factor alpha production in Ki-ras-transformed rat fibroblasts. FEBS Lett., 242, 363-367 (1989) https://doi.org/10.1016/0014-5793(89)80502-2
  75. Tortora, G., Pepe, S., Yokozaki, H., Meissner, S., and Cho- Chung, Y. S., Cooperative effect of 8-Cl-cAMP and rhGMCSF on the differentiation of HL-60 human leukemia cells. Biochem. Biophys. Res. Commun., 177, 1133-1140 (1991a) https://doi.org/10.1016/0006-291X(91)90657-S
  76. Tortora, G., Yokozaki, H., Pepe, S., Clair, T., and Cho-Chung, Y. S., Differentiation of HL-60 leukemia cells by type I regulatory subunit antisense oligodeoxynucleotide of cAMP-dependent protein kinase. Proc. Natl. Acad. Sci. USA, 88, 2011-2015 (1991b) https://doi.org/10.1073/pnas.88.5.2011
  77. Uhlmann, E., Oligonucleotide technologies: synthesis, production, regulations and applications. 29-30th November 2000, Hamburg, Germany. Expert. Opin. Biol. Ther., 1, 319-328 (2001) https://doi.org/10.1517/14712598.1.2.319
  78. Wang, Y. and Patel, D. J., Solution structure of a parallelstranded G-quadruplex DNA. J. Mol. Biol., 234, 1171-1183 (1993) https://doi.org/10.1006/jmbi.1993.1668
  79. Waters, J. S., Webb, A., Cunningham, D., Clarke, P. A., Raynaud, F., di Stefano, F., and Cotter, F. E., Phase I clinical and pharmacokinetic study of Bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma. J. Clin. Oncol., 18, 1812-1823 (2000) https://doi.org/10.1200/JCO.2000.18.9.1812
  80. Wickstrom, E., Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors. New York, Marcel Dekker (1998)
  81. Wyatt, J. R. and Stein, C. A., G-quartet inhibitory effects of phosphorothioate oligonucleotides, In L. Rabbani, Eds. Applications of Antisense Therapies to Restenosis. Norwell, Kluwer Acad (1999)
  82. Yang, W. L., Iacono, L., Tang, W. M., and Chin, K. V., Novel function of the regulatory subunit of protein kinase A: regulation of cytochrome c oxidase activity and cytochrome c release. Biochemistry, 37, 14175-14180 (1998) https://doi.org/10.1021/bi981402a
  83. Yokozaki, H., Budillon, A., Tortora, G., Meissner, S., Beaucage, S. L., Miki, K., and Cho-Chung, Y. S., An antisense oligodeoxynucleotide that depletes RI$\alpha$ subunit of cyclic AMP-dependent protein kinase induces growth inhibition in human cancer cells. Cancer Res., 53, 868-872 (1993)
  84. Young, M. R., Montpettit, I. M., Lozano, Y., Djordjevic, A., Devata, S., Matthews, I. P., Yedavalli, S., and Chejfec, G., Regulation of Lewis lung carcinoma invasion and metastasis by protein kinase A. Int. J. Cancer, 61, 104-109 (1995) https://doi.org/10.1002/ijc.2910610118
  85. Zamecnik, P. and Stephenson, M., Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc. Natl. Acad. Sci. USA, 75, 280-284 (1978) https://doi.org/10.1073/pnas.75.1.280
  86. Zhang, R., Zeng, X. F., Bowman, J. D., and Agrawal, S., Growth inhibition of human lung cancer A549 xenografts in nude mice following oral administration of mixed-backbone oligonucleotides targeted at protein kinase A. Proc. Am. Assoc. Cancer Res., 39, 3522 (1998)
  87. Zhao, Q., Temsamani, J., Zhou, R. Z., and Agrawal, S., Pattern and kinetics of cytokine production following administration of phosphorothioate oligonucleotides in mice. Antisense Nucleic Acid Drug Dev., 7, 495-502 (1997) https://doi.org/10.1089/oli.1.1997.7.495