Skip to main content
SpringerLink
Log in

Targeted therapy in the treatment of solid tumors: Practice contradicts theory

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

The basic principle of targeted therapy formulated about ten years ago consists in the design and application of drugs specifically directed against well-defined targets that are critical for tumor survival and not compromising for normal organs and tissues. The past decade has been marked by the appearance of an immense diversity of novel antitumor agents with claimed targeted action. Unfortunately, despite indisputable progress in clinical settings, some popular drugs against solid tumors (e.g. bevacizumab, trastuzumab, erlotinib, gefitinib) nominally assigned to targeted-action drugs, cannot actually be classified with this group being nonconforming to a priori stated goals of targeted therapy. The state-of-the-art and current problems in targeted therapy of solid tumors are reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CEP:

circulating endothelial precursors

EGFR:

epidermal growth factor receptor

HSC:

hemopoietic stem cells

NSCLC:

non-small cell lung cancer

VEGF:

vasoen-dothelial growth factor

References

  1. US Food and Drug Administration, Office of Combination Products (2003) Annual Report to Congress Federal Food, Drug, and Cosmetic Act as Amended by the Medical Device User Fee Act of 2002, National Press Office, Rockville, MD.

    Google Scholar 

  2. Brien, S. E., Zagzag, D., and Brem, S. (1989) Neurosurgery, 25, 715–719.

    Article  PubMed  CAS  Google Scholar 

  3. Folkman, J. (1990) J. Natl. Cancer Inst., 82, 4–6.

    Article  PubMed  CAS  Google Scholar 

  4. Fukumura, D., Xavier, R., Sugiura, T., Chen, Y., Park, E. C., Lu, N., Selig, M., Nielsen, G., Taksir, T., Jain, R. K., and Seed, B. (1998) Cell, 94, 715–725.

    Article  PubMed  CAS  Google Scholar 

  5. Peichev, M., Naiyer, A. J., Pereira, D., Zhu, Z., Lane, W. J., Williams, M., Oz, M. C., Hicklin, D. J., Witte, L., Moore, M. A. S., and Rafii, S. (2000) Blood, 95, 952–958.

    PubMed  CAS  Google Scholar 

  6. Rafii, S. (2000) J. Clin. Invest., 105, 17–19.

    Article  PubMed  CAS  Google Scholar 

  7. Folberg, R., Hendrix, M. J., and Maniotis, A. J. (2000) Am. J. Pathol., 156, 361–381.

    PubMed  CAS  Google Scholar 

  8. Chang, Y. S., di Tomaso, E., McDonald, D. M., Jones, R., Jain, R. K., and Munn, L. L. (2000) Proc. Natl. Acad. Sci. USA, 97, 14608–14613.

    Article  PubMed  CAS  Google Scholar 

  9. Dickson, P. V., Hamner, J. B., Sims, T. L., Fraga, C. H., Ng, C. Y. C., Rajasekeran, S., Hagedorn, N. L., McCarville, M. B., Stewart, C. F., and Davidoff, A. M. (2007) Clin. Cancer Res., 13, 3942–3950.

    Article  PubMed  CAS  Google Scholar 

  10. Shaked, Y., Emmenegger, U., Man, S., Cervi, D., Bertolini, F., Ben-David, Y., and Kerbel, R. S. (2005) Blood, 106, 3058–3061.

    Article  PubMed  CAS  Google Scholar 

  11. Colleoni, M., Rocca, A., Sandri, M. T., Zorzino, L., Masci, G., Nole, F., Peruzzotti, G., Robertson, C., Cinieri, S., de Braud, F., Viale, G., and Goldhirsch, A. (2002) Ann. Onc., 13, 73–80.

    Article  CAS  Google Scholar 

  12. Burstein, H. J., Spigel, D., Kindsvogel, K., Parker, L. M., Bunnell, C. A., Partridge, A. H., Come, S. E., Ryan, P. D., Gelman, R., and Winer, E. P. (2005) Breast Cancer Res. Treat., 94(Suppl. 1), S6 (abstract 4).

    Google Scholar 

  13. Senger, D. R., Galli, S. J., Dvorak, A. M., Perruzzi, C. A., Harvey, V. S., and Dvorak, H. F. (1983) Science, 219, 983–985.

    Article  PubMed  CAS  Google Scholar 

  14. Iliopoulos, O., Levy, A. P., Jiang, C., Kaelin, W. G., Jr., and Goldberg, M. A. (1996) Proc. Natl. Acad. Sci. USA, 93, 10595–10599.

    Article  PubMed  CAS  Google Scholar 

  15. Ferrara, N., Gerber, H. P., and LeCouter, J. (2003) Nat. Med., 9, 669–676.

    Article  PubMed  CAS  Google Scholar 

  16. Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., Berlin, J., Baron, A., Griffing, S., Holmgren, E., Ferrara, N., Fyfe, G., Rogers, B., Ross, R., and Kabbinavar, F. (2004) N. Engl. J. Med., 350, 2335–2342.

    Google Scholar 

  17. Giantonio, B. J., Catalano, P. J., Meropol, N. J., O’Dwyer, P. J., Mitchell, E. P., Alberts, S. R., Schwartz, M. A., and Benson, A. B., 3rd (2007) J. Clin. Oncol., 25, 1539–1544.

    Article  PubMed  CAS  Google Scholar 

  18. Miller, K. D. (2003) Clin. Breast Cancer, 3, 421–422.

    Article  PubMed  CAS  Google Scholar 

  19. Miller, K. D., Chap, L. I., Holmes, F. A., Cobleigh, M. A., Marcom, P. K., Fehrenbacher, L., Dickler, M., Overmoyer, B. A., Reimann, J. D., Sing, A. P., Langmuir, V., and Rugo, H. S. (2005) J. Clin. Oncol., 23, 792–799.

    Article  PubMed  CAS  Google Scholar 

  20. Sandler, A. B., Gray, R., Perry, M. C., Brahmer, J., Schiller, J. H., Dowlati, A., Lilenbaum, R., and Johnson, D. H. (2006) N. Engl. J. Med., 355, 2542–2550.

    Article  PubMed  CAS  Google Scholar 

  21. Burger, R. A., Sill, M. W., Monk, B. J., Greer, B. E., and Sorosky, J. I. (2007) J. Clin. Oncol., 25, 5165–5171.

    Article  PubMed  CAS  Google Scholar 

  22. Cannistra, S. A., Matulonis, U., Penson, R., Wenham, R., Armstrong, D., Burger, R. A., Mackey, H., Douglas, J., Hambleton, J., and McGuire, W. (2006) J. Clin. Oncol., 24, 257S.

    Google Scholar 

  23. Shalaby, F., Rossant, J., Yamaguchi, T. P., Gertsenstein, M., Wu, X. F., Breitman, M. L., and Schuh, A. C. (1995) Nature, 376, 62–66.

    Article  PubMed  CAS  Google Scholar 

  24. Fong, G. H., Zhang, L., Bryce, D. M., and Peng, J. (1999) Development, 126, 3015–3025.

    PubMed  CAS  Google Scholar 

  25. Zhukova, L., Zhukov, N., and Lichinitser, M. (2003) Byul. Eksp. Biol. Med., 135, 478–481.

    Article  CAS  Google Scholar 

  26. Chung, G. G., Yoon, H. H., Zerkowski, M. P., Ghosh, S., Thomas, L., Harigopal, M., Charette, L. A., Salem, R. R., Camp, R. L., Rimm, D. L., and Burtness, B. A. (2006) Cancer, 106, 1677–1684.

    Article  PubMed  CAS  Google Scholar 

  27. Seto, T., Higashiyama, M., Funai, H., Imamura, F., Uematsu, K., Seki, N., Eguchi, K., Yamanaka, T., and Ichinose, Y. (2006) Lung Cancer, 53, 91–96.

    Article  PubMed  Google Scholar 

  28. Carrivick, L., Rogers, S., Clark, J., Campbell, C., Girolami, M., and Cooper, C. (2006) J. R. Soc. Interface, 3, 367–381.

    Article  PubMed  CAS  Google Scholar 

  29. Fan, F., Wey, J. S., McCarty, M. F., Belcheva, A., Liu, W., Bauer, T. W., Somcio, R. J., Wu, Y., Hooper, A., Hicklin, D. J., and Ellis, L. M. (2005) Oncogene, 24, 2647–2653.

    Article  PubMed  CAS  Google Scholar 

  30. Mendelsohn, J., and Baselga, J. (2003) J. Clin. Oncol., 21, 2787–2799.

    Article  PubMed  CAS  Google Scholar 

  31. Olayioye, M. A., Neve, R. M., Lane, H. A., and Hynes, N. E. (2000) EMBO J., 19, 3159–3167.

    Article  PubMed  CAS  Google Scholar 

  32. Graus-Porta, D., Beerli, R. R., Daly, J. M., and Hynes, N. E. (1997) EMBO J., 16, 1647–1655.

    Article  PubMed  CAS  Google Scholar 

  33. Citri, A., Skaria, K. B., and Yarden, Y. (2003) Exp. Cell Res., 284, 54–65.

    Article  PubMed  CAS  Google Scholar 

  34. Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., and McGuire, W. L. (1987) Science, 235, 177–182.

    Article  PubMed  CAS  Google Scholar 

  35. Toikkanen, S., Helin, H., Isola, J., and Joensuu, H. (1992) J. Clin. Oncol., 10, 1044–1048.

    PubMed  CAS  Google Scholar 

  36. Papaldo, P., Fabi, A., Ferretti, G., Mottolese, M., Cianciulli, A. M., di Cocco, B., Pino, M. S., Carlini, P., di Cosimo, S., Sacchi, I., Sperduti, I., Nardoni, C., and Cognetti, F. (2006) Ann. Onc., 17, 630–636.

    Article  CAS  Google Scholar 

  37. Chia, S., Speers, C., and Kang, A. (2003) Proc. Am. Soc. Clin. Oncol., 22, 6.

    Google Scholar 

  38. Sliwkowski, M. X., Lofgren, J. A., Lewis, G. D., Hotaling, T. E., Fendly, B. M., and Fox, J. A. (1999) Semin. Oncol., 26(Suppl. 12), S60–S70.

    Google Scholar 

  39. Arnould, L., Gelly, M., Penault-Llorca, F., Benoit, L., Bonnetain, F., Migeon, C., Cabaret, V., Fermeaux, V., Bertheau, P., Garnie, J., Jeannin, J. F., and Coudert, B. (2006) Br. J. Cancer, 94, 259–267.

    Article  PubMed  CAS  Google Scholar 

  40. Gennari, R., Menard, S., Fagnoni, F., Ponchio, L., Scelsi, M., Tagliabue, E., Castiglioni, F., Villani, L., Magalotti, C., Gibelli, N., Oliviero, B., Ballardini, B., da Prada, G., Zambelli, A., and Costa, A. (2004) Clin. Cancer Res., 10, 5650–5655.

    Article  PubMed  CAS  Google Scholar 

  41. Cooley, S., Burns, L. J., Repka, T., and Miller, J. S. (1999) Exp. Hematol., 27, 1533–1541.

    Article  PubMed  CAS  Google Scholar 

  42. Stockmeyer, B., Beyer, T., Neuhuber, W., Repp, R., Kalden, J. R., Valerius, T., and Herrmann, M. (2003) J. Immunol., 171, 5124–5129.

    PubMed  CAS  Google Scholar 

  43. Saez, R., Molina, M. A., Ramsey, E. E., Rojo, F., Keenan, E. J., Albanell, J., Lluch, A., Garcia-Conde, J., Baselga, J., and Clinton, G. M. (2006) Clin. Cancer Res., 12, 424–431.

    Article  PubMed  CAS  Google Scholar 

  44. Pietras, R. J., Pegram, M. D., Finn, R. S., Maneval, D. A., and Slamon, D. J. (1998) Oncogene, 17, 2235–2249.

    Article  PubMed  CAS  Google Scholar 

  45. Cobleigh, M. A., Vogel, C. L., Tripathy, D., Robert, N. J., Scholl, S., Fehrenbacher, L., Wolter, J. M., Paton, V., Shak, S., Lieberman, G., and Slamon, D. J. (1999) J. Clin. Oncol., 17, 2639–2648.

    PubMed  CAS  Google Scholar 

  46. Vogel, C. L., Cobleigh, M. A., Tripathy, D., Gutheil, J. C., Harris, L. N., Fehrenbacher, L., Slamon, D. J., Murphy, M., Novotny, W. F., Burchmore, M., Shak, S., Stewart, S. J., and Press, M. (2002) J. Clin. Oncol., 20, 719–726.

    Article  PubMed  CAS  Google Scholar 

  47. Slamon, D. J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., Pegram, M., Baselga, J., and Norton, L. (2001) N. Engl. J. Med., 344, 783–792.

    Article  PubMed  CAS  Google Scholar 

  48. Marty, M., Cognetti, F., Maraninchi, D., Snyder, R., Mauriac, L., and Tubiana-Hulin, M. (2005) J. Clin. Oncol., 23, 4265–4274.

    Article  PubMed  CAS  Google Scholar 

  49. Piccart-Gebhart, M. J., Procter, M., Leyland-Jones, B., Goldhirsch, A., Untch, M., Smith, I., Gianni, L., Baselga, J., Bell, R., Jackisch, C., Cameron, D., Dowsett, M., Barrios, C. H., Steger, G., Huang, C., Andersson, M., Inbar, M., Lichinitser, M., Lang, I., Nitz, U., Iwata, H., Thomssen, C., Lohrisch, C., Suter, T. M., Rruschoff, J., Suto, T., Greatorex, V., Ward, C., Straehle, C., McFadden, E., Dolci, M. S., and Gelber, R. D. (2005) N. Engl. J. Med., 353, 1659–1672.

    Article  PubMed  CAS  Google Scholar 

  50. Romond, E. H., Perez, E. A., Bryant, J., Suman, V. J., Geyer, C. E., Davidson, N. E., Tan-Chiu, E., Martino, S., Paik, S., Kaufman, P. A., Swain, S. M., Pisansky, T. M., Fehrenbacher, L., Kutteh, L. A., Vogel, V. G., Visscher, D. W., Yothers, G., Jenkins, R. B., Brown, A. M., Dakhil, S. R., Mamounas, E. P., Lingle, W. L., Klein, P. M., Ingle, J. N., and Wolmark, N. (2005) N. Engl. J. Med., 353, 1673–1684.

    Article  PubMed  CAS  Google Scholar 

  51. Paik, S., Kim, C., Jeong, J., Geyer, C. E., Romond, E. H., Mejia-Mejia, O., Mamounas, E. P., Wickerham, D., Costantino, J. P., and Wolmark, N. (2007) Proc. Am. Soc. Clin. Oncol., 25, 5s (abstract 511).

    Google Scholar 

  52. Brabender, J., Danenberg, K. D., Metzger, R., Schneider, P. M., Park, J., Salonga, D., Holscher, A. H., and Danenberg, P. (2001) Clin. Cancer Res., 7, 1850–1855.

    PubMed  CAS  Google Scholar 

  53. Baselga, J. (2000) Signal, 1, 12–21.

    Article  Google Scholar 

  54. Woodburn, J. R. (1999) Pharmacol. Ther., 82, 241–250.

    Article  PubMed  CAS  Google Scholar 

  55. Baselga, J. (2002) The Oncologis, 7(Suppl. 4), 2–8.

    Article  CAS  Google Scholar 

  56. Fukuoka, M., Yano, S., Giaccone, G., Tamura, T., Nakagawa, K., Douillard, J., Nishiwaki, Y., Vansteenkiste, J., Kudoh, S., Rischin, D., Eek, R., Horai, T., Noda, K., Takata, I., Smit, E., Averbuch, S., Macleod, A., Feyereislova, A., Dong, R., and Baselga, J. (2003) J. Clin. Oncol., 21, 2227–2229.

    Article  CAS  Google Scholar 

  57. Perez-Soler, R., Chachoua, A., Hammond, L. A., Rowinsky, E. K., Huberman, M., Karp, D., Rigas, J., Clark, G. M., Santabσrbara, P., and Bonomi, P. (2004) J. Clin. Oncol., 22, 3238–3247.

    Article  PubMed  CAS  Google Scholar 

  58. Thatcher, N., Chang, A., Parikh, P., Pemberton, K., and Archer, V. (2005) Lancet, 366, 1527–1537.

    Article  PubMed  CAS  Google Scholar 

  59. Shepherd, F. A., Rodrigues Pereira, J., Ciuleanu, T., Tan, E. H., Hirsh, V., Thongprasert, S., Campos, D., Maoleekoonpiroj, S., Smylie, M., Martins, R., van Kooten, M., Dediu, M., Findlay, B., Tu, D., Johnston, D., Bezjak, A., Clark, G., Santabarbara, P., and Seymour, L. (2005) N. Engl. J. Med., 353, 123–132.

    Article  PubMed  CAS  Google Scholar 

  60. Giaccone, G., Herbs, R. S., Manegold, C., Scagliotti, G., Rosell, R., Miller, V., Natale, R. B., Schiller, J. H., von Pawel, J., Pluzanska, A., Gatzemeier, U., Grous, J., Ochs, J. S., Averbuch, S. D., Wolf, M. K., Rennie, P., Fandi, A., and Johnson, D. H. (2004) J. Clin. Oncol., 22, 777–784.

    Article  PubMed  CAS  Google Scholar 

  61. Herbst, R. S., Giaccone, G., Schiller, J. H., Natale, R. B., Miller, V., Manegold, C., Scagliotti, G., Rosell, R., Oliff, I., Reeves, J. A., Wolf, M. K., Krebs, A. D., Averbuch, S. D., Ochs, J. S., Grous, J., Fandi, A., and Johnson, D. H. (2004) J. Clin. Oncol., 22, 785–794.

    Article  PubMed  CAS  Google Scholar 

  62. Herbst, R. S., Prager, D., Hermann, R., Fehrenbacher, L., Johnson, B. E., Sandler, A., Kris, M. G., Tran, H. T., Klein, P., Li, X., Ramies, D., Johnson, D. H., and Miller, V. A. (2005) J. Clin. Oncol., 23, 5892–5899.

    Article  PubMed  CAS  Google Scholar 

  63. Gatzemeier, U., Pluzanska, A., Szczesna, A., Kaukel, E., Roubec, J., de Rosa, F., Milanowski, J., Karnicka-Mlodkowski, H., Pesek, M., Serwatowski, P., Ramlau, R., Janaskova, T., Vansteenkiste, J., Strausz, J., Manikhas, G. M., and von Pawel, J. (2007) J. Clin. Oncol., 25, 1545–1552.

    Article  PubMed  CAS  Google Scholar 

  64. Bell, D. W., Lynch, T. J., Haserlat, S. M., Harris, P. L., Okimoto, R. A., Brannigan, B. W., Sgroi, D. C., Muir, B., Riemenschneider, M. J., Iacona, R., Krebs, A. D., Johnson, D. H., Giaccone, G., Herbst, R. S., Manegold, C., Fukuoka, M., Kris, M. G., Baselga, J., Ochs, J. S., and Haber, D. A. (2005) J. Clin. Oncol., 23, 8081–8092.

    Article  PubMed  CAS  Google Scholar 

  65. Tsao, M. S., Sakurada, A., Cutz, J. C., Zhu, C., Kamel-Reid, S., Squire, J., Lorimer, I., Zhang, T., Liu, N., Daneshmand, M., Marrano, P., da Cunha Santos, G., Lagarde, A., Richardson, F., Seymour, L., Whitehead, M., Ding, K., Pater, J., and Shepherd, F. A. (2005) N. Engl. J. Med., 353, 133–144.

    Article  PubMed  CAS  Google Scholar 

  66. Hirsch, F. R., Varella-Garcia, M., Bunn, F. A., Franklin, W. A., Dziadziuszko, R., Thatcher, N., Chang, A., Parikh, P., Rodrigues Pereira, J., Ciuleanu, T., von Pawel, J., Watkins, C., Flannery, A., Ellison, G., Donald, E., Knight, L., Parums, D., Botwood, N., and Holloway, B. (2006) J. Clin. Oncol., 24, 5034–5042.

    Article  PubMed  CAS  Google Scholar 

  67. Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., Louis, D. N., Christiani, D. C., Settleman, J., and Haber, D. A. (2004) N. Engl. J. Med., 350, 2129–2139.

    Article  PubMed  CAS  Google Scholar 

  68. Paez, J. G., Janne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., Naoki, K., Sasaki, H., Fujii, Y., Eck, M. J., Sellers, W. R., Johnson, B. E., and Meyerson, M. (2004) Science, 304, 1497–1500.

    Article  PubMed  CAS  Google Scholar 

  69. Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., Singh, B., Heelan, R., Rusch, V., Fulton, L., Mardis, E., Kupfer, D., Wilson, R., Kris, M., and Varmus, H. (2004) Proc. Natl. Acad. Sci. USA, 101, 13306–13311.

    Article  PubMed  CAS  Google Scholar 

  70. Sequist, L. V., Bell, D. W., Lynch, T. J., and Haber, D. A. (2007) J. Clin. Oncol., 25, 587–595.

    Article  PubMed  CAS  Google Scholar 

  71. Epstein, R. J. (2007) Cancer Met. Rev., 26, 443–452.

    Article  CAS  Google Scholar 

  72. Cobleigh, M. A., Langmuir, V. K., Sledge, G. W., Miller, K. D., Haney, L., Novotny, W. F., Reimann, J. D., and Vassel, A. (2003) Semin. Oncol., 30(Suppl. 16), 117–124.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Federal Research-Clinical Center for Pediatric Hematology, Oncology, and Immunology, Ministry of Health Care and Social Security of the Russian Federation, Leninsky pr. 117, Bldg. 2, 117997, Moscow, Russia

    N. V. Zhukov

  2. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Kashirskoe Shosse 24, 115478, Moscow, Russia

    S. A. Tjulandin

Authors
  1. N. V. Zhukov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. A. Tjulandin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. V. Zhukov.

Additional information

Original Russian Text © N. V. Zhukov, S. A. Tjulandin, 2008, published in Biokhimiya, 2008, Vol. 73, No. 5, pp. 751–768.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhukov, N.V., Tjulandin, S.A. Targeted therapy in the treatment of solid tumors: Practice contradicts theory. Biochemistry Moscow 73, 605–618 (2008). https://doi.org/10.1134/S000629790805012X

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S000629790805012X

Key words

Search

Navigation