Skip to main content

Advertisement

SpringerLink
Log in

Gene therapeutic approaches for medullary thyroid carcinoma treatment

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Medullary thyroid carcinoma (MTC), a neoplasm of thyroid C-cells, is characterized by dominant activating mutations in the RET proto-oncogene. Currently therapy is restricted to surgical removal of all neoplastic tissue lacking alternative forms of treatment such as chemotherapy or radiotherapy. Therefore MTC is a particularly attractive target for gene therapeutic approaches. Many promising gene therapy strategies have been used in various animal models of MTC, showing enhanced antitumoral efficacy, and these will hopefully extend our current standard of care in the future. These approaches can tentatively be subdivided into four groups: (a) Inhibition of oncogenic RET signaling, (b) suicide gene therapy, (c) immunotherapy, and (d) combination of immunotherapy and suicide approaches. To block oncogenic signal transduction dominant-negative RET mutants were delivered into tumor cells and found to possess strong antineoplastic activity, including tumor growth suppression and increased animal survival. Suicide gene therapeutic approaches applied to MTC treatment featured either gene transfer of herpes simplex virus thymidine kinase with concomitant application of ganciclovir or delivery of nitric oxide synthase II. Here antitumor effects were attributed to the occurrence of substantial bystander activities. Immunotherapy approaches comprised stimulation of immune response by delivery of interleukin 2 or 12. Finally, treatment with herpes simplex virus thymidine kinase/ganciclovir in combination with interleukin 2 was found to be superior over either treatment alone. This review discusses the various gene therapeutic approaches applied to MTC treatment in detail, gives an overview on the diverse vector systems used to achieve efficient transduction of thyroid cancer cells, and points out the strategies employed to accomplish target cell selective gene expression thereby contributing to enhanced safety of gene therapy for MTC

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

Fig. 1.

Similar content being viewed by others

Abbreviations

GCV :

Ganciclovir

HSV-TK :

Herpes simplex virus thymidine kinase

IL :

Interleukin

MEN :

Multiple endocrine neoplasia

MTC :

Medullary thyroid carcinoma

NK :

Natural killer

NOS II :

Nitric oxide synthase II

RET :

Rearranged during transfection

References

  1. Vitale G, Caraglia M, Ciccarelli A, Lupoli G, Abbruzzese A, Tagliaferri P, Lupoli G (2001) Current approaches and perspectives in the therapy of medullary thyroid carcinoma. Cancer 91:1797–1808

    Article  CAS  PubMed  Google Scholar 

  2. Hundahl SA, Fleming ID, Fremgen AM, Menck HR (1998) A national cancer database report on 53856 cases of thyroid carcinoma treated in the US 1985–1995. Cancer 83:2638–2648

    Article  CAS  PubMed  Google Scholar 

  3. Eng C (1999) RET proto-oncogene in the development of human cancer. J Clin Oncol 17:380–393

    CAS  PubMed  Google Scholar 

  4. Hazard JB (1977) The C-cells (parafollicular cells) of the thyroid gland and medullary thyroid carcinoma. J Pathol 88:213–250

    CAS  Google Scholar 

  5. Orlandi F, Caraci P, Mussa A, Saggiorato E, Pancani G, Angeli A (2001) Treatment of medullary thyroid carcinoma: an update. Endocr Relat Cancer 8:135–147

    CAS  PubMed  Google Scholar 

  6. Ponder BA, Smith D (1996) The MEN II syndromes and the role aof the ret proto-oncogene. Adv Cancer Res 70:179–222

    CAS  PubMed  Google Scholar 

  7. Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BA (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:548–560

    Google Scholar 

  8. Takahashi M (2001) The RET/GDNF signaling pathway and human diseases. Cytokine Growth Factor Rev 12:361–373

    Article  CAS  PubMed  Google Scholar 

  9. Asai N, Iwashita T, Matsuyama M, Takahashi M (1995) Mechanism of activation of ret proto-oncogene by multiple endocrine neoplasia 2A mutation. Mol Cell Biol 15:1613–1619

    Google Scholar 

  10. Gimm O (2001) Thyroid cancer. Cancer Lett 163:143–156

    Article  CAS  PubMed  Google Scholar 

  11. Frilling A, Weber F, Tecklenborg C, Broelsch CE (2003) Prophylactic thyroidectomy in multiple endocrine neoplasia: the impact of molecular mechanisms of the RET proto-oncogene. Langenbecks Arch Surg 388:17–26

    PubMed  Google Scholar 

  12. Schmutzler C, Koehrle J (2000) Innovative strategies for the treatment of thyroid cancer. Eur J Endocrinol 143:15–24

    CAS  PubMed  Google Scholar 

  13. Willis AC, Chen X (2002) The promise and obstacle of p53 as a cancer therapeutic agent. Curr Mol Med 2:329–345

    CAS  PubMed  Google Scholar 

  14. Herfarth KKF, Wick MR, Marshall HN, Gartner E, Lum S, Moley JF (1997) Absence of TP53 alterations in pheochromocytomas and medullary thyroid carcinomas. Genes Chromosom Cancer 20:24–29

    Article  CAS  PubMed  Google Scholar 

  15. Yane K, Konishi N, Kitahori Y, Naito H, Koaichi K, Ohnishi T, Miyahara H, Matsunaga T, Hiasa Y (1996) Lack of p16/CKDN2 alterations in thyroid carcinomas. Cancer Lett 101:85–92

    Article  CAS  PubMed  Google Scholar 

  16. Segouffin-Cariou C, Billaud M (2000) Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathway. J Biol Chem 275:3568–3576

    Article  CAS  PubMed  Google Scholar 

  17. Vivanco I, Sawyers CL (2002) The phosphatidyl 3-kinase Akt pathway in human cancer. Nat Rev Cancer 2:489–501

    Article  CAS  PubMed  Google Scholar 

  18. Weering DHJ van, Bos JL (1998) Signal transduction by the receptor tyrosine kinase RET. Recent Results Cancer Res 154:271–281

    PubMed  Google Scholar 

  19. Marshall GM, Peaston AE, Hocker JE, Smith SA, Hansford LM, Tobias V, Norris MD, Haber M, Smith DP, Lorenzo MJ, Ponder BA, Hancock JF (1997) Expression of multiple endocrine neoplasia 2B RET in neuroblastoma cells alters cell adhesion in vitro, enhances metastatic behaviour in vivo and activates Jun kinase. Cancer Res 57:5399–5405

    CAS  PubMed  Google Scholar 

  20. Lui VW, He Y, Huang L (2001) Specific down-regulation of HER-2/neu mediated by a chimeric U6 hammerhead ribozyme results in growth inhibition of human ovarian carcinoma. Mol Ther 3:169–177

    Article  CAS  PubMed  Google Scholar 

  21. Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy M, Shen Q, O'Hagan R, Pantginis J, Zhou H, Horner JW, Cordon-Cardo C, Yancopoulos GD, DePinho RA (1999) Essential role for oncogenic Ras in tumor maintenance. Nature 400:468–472

    Google Scholar 

  22. Drosten M, Frilling A, Stiewe T, Pützer BM (2002) A new therapeutic approach in medullary thyroid cancer treatment: inhibition of oncogenic RET signaling by adenoviral vector-mediated expression of a dominant-negative RET mutant. Surgery 132:991–997

    Article  PubMed  Google Scholar 

  23. Drosten M, Stiewe T, Pützer BM (2003) Antitumor capacity of a dominant-negative RET proto-oncogene mutant in a medullary thyroid carcinoma model. Hum Gene Ther (in press)

  24. Cosma MP, Cardone M, Carlomagno F, Colantuoni V (1998) Mutations in the extracellular domain cause RET loss of function by a dominant negative mechanism. Mol Cell Biol 18:3321–3329

    CAS  PubMed  Google Scholar 

  25. Messina M, Yu DM, Learoyd DL, Both GW, Molloy PL, Robinson BG (2000) High level, tissue-specific expression of a modified calcitonin/calcitonin gene-related peptide promoter in a human medullary thyroid carcinoma cell line. Mol Cell Endocrinol 164:219–224

    Article  CAS  PubMed  Google Scholar 

  26. Parthasarathy R, Cote GJ, Gagel RF (1999) Hammerhead ribozyme-mediated inactivation of mutant RET in medullary thyroid carcinoma. Cancer Res 59:3911–3914

    CAS  PubMed  Google Scholar 

  27. Hennige AM, Lammers R, Höppner W, Arlt D, Strack V, Teichmann R, Machicao F, Ullrich A, Häring HU, Kellerer M (2001) Inhibition of Ret oncogene activity by the protein tyrosine phosphatase SHP1. Endocrinology 143:4441–4447

    Google Scholar 

  28. Qiao S, Iwashita T, Furukawa T, Yamamoto M, Sobue G, Takahashi M (2001) Differential effects of leukocyte common antigen-related protein on biochemical and biological activities of RET-MEN2A and RET-MEN2B mutant proteins. J Biol Chem 276:9460–9467

    Article  CAS  PubMed  Google Scholar 

  29. Aghi M, Hochberg F, Breakefield XO (2000) Prodrug activation enzymes in cancer gene therapy. J Gene Med 2:148–164

    Article  CAS  PubMed  Google Scholar 

  30. Molten FL (1986) Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: a paradigm for a prospective cancer control strategy. Cancer Res 46:5276–5281

    CAS  PubMed  Google Scholar 

  31. Fillat C, Carrio M, Cascante A, Sangro B (2003) Suicide gene therapy mediated by the Herpes simplex virus thymidin kinase gene/Ganciclovir system: fifteen years of application. Curr Gene Ther 3:13–26

    CAS  PubMed  Google Scholar 

  32. Dillen IJ van, Mulder NH, Vaalburg V, de Vries EF, Hospers GA (2002) Influence of the bystander on HSV-tk/GCV gene therapy. A review. Curr Gene Ther 2:307–322

    PubMed  Google Scholar 

  33. Ishii-Morita H, Agbaria R, Mullen CA, Hirano H, Koeplin DA, Ram Z, Oldfield EH, Johns DG, Blaese RM (1997) Mechanism of 'bystander effect' killing in the herpes simplex virus thymidine kinase gene therapy model of cancer treatment. Gene Ther 4:244–251

    Article  CAS  PubMed  Google Scholar 

  34. Fick J, Barker FG, Dazin P, Westphale EM, Beyer EC, Isreal MA (1995) The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro. Proc Natl Acad Sci USA 92:11071–11075

    CAS  PubMed  Google Scholar 

  35. Minemura K, Takeda T, Minemura K, Nagasawa T, Zhang R, Leopardi R, DeGroot LJ (2000) Cell-specific induction of sensitivity to ganciclovir in medullary thyroid carcinoma by adenovirus-mediated gene transfer of Herpes simplex virus thymidine kinase. Endocrinology 141:1814–1822

    CAS  PubMed  Google Scholar 

  36. Zhang R, DeGroot LJ (2000) Gene therapy of established medullary thyroid carcinoma with herpes simplex viral thymidine kinase in a rat tumor model: relationship of bystander effect and antitumor efficacy. Thyroid 10:313–319

    CAS  PubMed  Google Scholar 

  37. Jiang S, Altmann A, Grimm D, Kleinschmidt JA, Schilling T, Germann C, Haberkorn U (2001) Tissue-specific gene expression in medullary thyroid carcinoma cells employing calcitonin regulatory elements and AAV vectors. Cancer Gene Ther 8:469–472

    Article  CAS  PubMed  Google Scholar 

  38. Nathan C, Xie QW (1994) Nitric oxide synthases: roles, tolls and controls. Cell 78:915–918

    CAS  PubMed  Google Scholar 

  39. Drapier JC, Hibbs JB Jr (1988) Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells. J Immunol 140:2829–2838

    CAS  PubMed  Google Scholar 

  40. Burney S, Tamir S, Gal A, Tannenbaum SR (1997) A mechanistic analysis of niric oxide-induced cellular toxicity. Nitric Oxide 1:130–144

    CAS  PubMed  Google Scholar 

  41. Lepoivre M, Chenais B, Yapo A, Lemaire G, Thelander L, Tenu JP (1990) Alterations of ribonucleotide activity following induction of the nitrite-generation pathway in adenocarcinoma cells. J Biol Chem 265:14143–14149

    CAS  PubMed  Google Scholar 

  42. Lancaster JF Jr (1994) Stimulation of the diffusion and reaction of the endogenously produced nitric oxide. Proc Natl Acad Sci USA 91:8137–8141

    CAS  PubMed  Google Scholar 

  43. Schwentker A, Billiar TR (2002) Inducible nitric oxide synthase: from cloning to therapeutic applications. World J Surg 26:772–778

    Article  PubMed  Google Scholar 

  44. Soler MN, Bobe P, Benihoud K, Lemaire G, Roos BA, Lausson S (2000) Gene therapy of rat medullary thyroid cancer by naked nitric oxide synthase II DNA injection. J Gene Med 2:344–352

    Article  CAS  PubMed  Google Scholar 

  45. Messina M, Yu DM, Both GW, Molloy PL, Robinson BG (2003) Calcitonin-specific transcription and splicing targets gene-directed enzyme prodrug therapy to medullary thyroid carcinoma cells. J Clin Endocrinol Metab 88:1310–1318

    Article  CAS  PubMed  Google Scholar 

  46. Parker WB, Allan PW, Shaddix SC, Rose LM, Speegle HF, Gillespie GY, Bennett LL Jr (1998) Metabolism and metabolic actions of 6-methylpurine and 2-fluoroadenine inhuman cells. Biochem Pharmacol 55:1673–1681

    Article  CAS  PubMed  Google Scholar 

  47. Khong HP, Restifo NP (2002) Natural selection of tumor variants in the generation of 'tumor escape' phenotypes. Nat Immunol 3:999–1005

    Article  CAS  PubMed  Google Scholar 

  48. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991–998

    Article  CAS  PubMed  Google Scholar 

  49. Parney IF, Chang LJ (2003) Cancer immunogene therapy: a review. J Biomed Sci 10:37–43

    Article  CAS  PubMed  Google Scholar 

  50. Haupt K, Siegel F, Lu M, Yang D, Hilken G, Mann K, Roggendorf M, Saller B (2001) Induction of a cellular and humoral immune response against Preprocalcitonin by genetic immunisation: a potential new treatment for medullary thyroid carcinoma. Endocrinology 142:1017–1023

    CAS  PubMed  Google Scholar 

  51. Addison CL, Braciak T, Ralston R, Muller WJ, Gauldie J, Graham FL (1995) Intratumoral injection of an adenovirus encoding interleukin-2 induces regression an immunity in a murine breast cancer model. Proc Natl Acad Sci USA 92:8522–8526

    CAS  PubMed  Google Scholar 

  52. Rosenberg SA (2001) Progress in human tumour immunology and immunotherapy. Nature 411:380–384

    CAS  PubMed  Google Scholar 

  53. Lausson S, Fournes B, Borrel C, Milhaud G, Treilhou-Lahille F (1996) Immune response against medullary thyroid carcinoma (MTC) induced by parental and/or interleukin-2-secreting MTC cells in a rat model of human familial medullary thyroid carcinoma. Cancer Immunol Immunother 43:116–123

    Article  CAS  PubMed  Google Scholar 

  54. Zhang R, Minemura K, DeGroot LJ (1998) Immunotherapy for medullary thyroid carcinoma by a replication-defective adenovirus transducing murine interleukin-2. Endocrinology 139:601–608

    CAS  PubMed  Google Scholar 

  55. Zhang R, Baunoch D, DeGroot LJ (1998) Genetic immunotherapy for medullary thyroid carcinoma: destruction of tumors in mice by in vivo delivery of adenoviral vector transducing the murine interleukin-2 gene. Thyroid 8:1137–1146

    CAS  PubMed  Google Scholar 

  56. Zhang R, Straus FH, DeGroot LJ (1999) Effective genetic therapy of established medullary thyroid carcinomas with murine interleukin-2: dissemination and cytotoxicity studies in a rat tumor model. Endocrinology 140:2152–2158

    CAS  PubMed  Google Scholar 

  57. Wolf SF, Temple PA, Kobayashi M, Young D, Dicig M, Lowe L, Dzialo R, Fitz L, Hewick RM, Kelleher K, Herrmann SH, Clark SC, Azzoni L, Chan SH, Trinchieri G, Perussia B (1991) Cloning of cDNA for natural killer cell stimulating factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol 146:3074–3081

    CAS  PubMed  Google Scholar 

  58. Trinchieri G (1995) Interleukin-12: a proinflammatory cytokine with immunoregulatory function that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 13:251–276

    CAS  PubMed  Google Scholar 

  59. Zitvogel L, Tahara H, Cai Q, Storkus W, Muller G, Wolf SF, Gately M, Robbins PD, Lotze MT (1994) Construction and characterization of retroviral vectors expressing biologically active human interleukin-12. Hum Gene Ther 5:1493–1506

    CAS  PubMed  Google Scholar 

  60. Melero I, Mazzolini G, Narvaiza I, Qian C, Chen L, Prieto J (2001) IL-12 gene therapy for cancer: in synergy with other immunotherapies. Trends Immunol 22:113–115

    CAS  PubMed  Google Scholar 

  61. Orange JS, Salazar-Mather TP, Opal SM, Spencer RL, Miller AH, McEwan BS, Biron CA (1995) Mechanism of interleukin 12-mediated toxicities during experimental viral infections: role of tumor necrosis factor and glucocorticoids. J Exp Med 181:901–914

    CAS  PubMed  Google Scholar 

  62. Zhang R, DeGroot LJ (2000) Genetic immunotherapy of established tumours with adenoviral vectors transducing murine interleukin-12 (mIL-12) subunits in a rat medullary thyroid carcinoma model. Clin Endocrinol (Oxf) 52:687–694

    Google Scholar 

  63. Yamazaki M, Zhang R, Straus FH, Messina M, Robinson BG, Hashizume K, DeGroot LJ (2002) Effective gene therapy for medullary thyroid carcinoma using recombinant adenovirus inducing tumor-specific expression of interleukin-12. Gene Ther 9:64–74

    Article  CAS  PubMed  Google Scholar 

  64. Soler MN, Milhaud G, Lekmine F, Treilhou-Lahille F, Klatzmann D, Lausson S (1999) Treatment of medullary thyroid carcinoma by combined expression of suicide and interleukin-2 genes. Cancer Immunol Immunother 48:91–99

    Article  CAS  PubMed  Google Scholar 

  65. Zhang R, DeGroot LJ (2001) An adenoviral vector expressing functional heterogeneous proteins herpes simplex viral thymidine kinase and human interleukin-2 has enhanced in vivo antitumor activity against medullary thyroid carcinoma. Endocr Relat Cancer 8:315–325

    CAS  PubMed  Google Scholar 

  66. Hinze R, Gimm O, Taubert H, Bauer G, Dralle H, Holzhausen HJ, Rath FW (2000) Regulation of proliferation and apoptosis in sporadic and heretitary medullary thyroid carcinomas and their putative precurser lesions. Virchows Arch 437:256–263

    Article  CAS  PubMed  Google Scholar 

  67. Shen C, Buck AK, Liu X, Winkler M, Reske SN (2003) Gene silencing by adenovirus-delivered siRNA. FEBS Lett 539:111–114

    Article  CAS  PubMed  Google Scholar 

  68. Cohen MS, Hussain HB, Moley JF (2002) Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors. Surgery 132:960–966

    Article  PubMed  Google Scholar 

  69. Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, Ryan AJ, Fontanini G, Fusco A, Santoro M (2002) ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 62:7284–7290

    CAS  PubMed  Google Scholar 

  70. Stewart AK, Lassam NJ, Quirt IC, Bailey DJ, Rotstein LE, Krajden M, Dessureault S, Gallinger S, Cappe D, Wan Y, Addison CL, Moen RC, Gauldie J, Graham FL (1999) Adenovector-mediated gene delivery of interleukin-2 in metastatic breast cancer and melanoma: results of a phase 1 clinical trial. Gene Ther 6:350–363

    CAS  PubMed  Google Scholar 

  71. DeGroot LJ, Zhang R (2001) Clinical review 131. Gene Therapy for thyroid cancer: where do we stand? J Clin Endocrinol Metab 86:2923–2928

    Google Scholar 

  72. Scappaticci FA (2002) Mechanisms and future directions for angiogenesis based-cancer therapies. J Clin Oncol 20:3906–3927

    Article  PubMed  Google Scholar 

  73. Chiocca EA (2002) Oncolytic viruses. Nat Rev Cancer 2:938–950

    Article  PubMed  Google Scholar 

  74. Nemunaitis J, Ganly I, Khuri F, Arseneau J, Kuhn J, McCarty T, Landers S, Maples P, Romel L, Randlev B, Reid T, Kaye S, Kirn D (2000) Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: a phase II trial. Cancer Res 60:6359–6366

    CAS  PubMed  Google Scholar 

  75. Rothmann T, Hengstermann A, Whitaker NJ, Scheffner M, zur Hausen H (1998) Replication of ONYX-015, a potential anticancer adenovirus, is independent of p53 status in tumor cells. J Virol 72:9470–9478

    CAS  PubMed  Google Scholar 

  76. Balague C, Noya F, Alemany R, Chow LT, Curiel DT (2001) Human papillomavirus E6E7-mediated adenovirus cell killing: selectivity of mutant adenovirus replication in organotypic cultures of human keratinocytes. J Virol 75:7602–7611

    Article  CAS  PubMed  Google Scholar 

  77. Li Y, Yu DC, Chen Y, Amin P, Zhang H, Nguyen N, Henderson DR (2001) A hepatocellular carcinoma-specific adenovirus variant, CV890, eliminates distant human liver tumors in combination with doxorubicin. Cancer Res 61:6428–6436

    CAS  PubMed  Google Scholar 

  78. Wickham TJ (2003) Ligand-directed targeting of genes to the site of disease. Nat Med 9:135–139

    Article  CAS  PubMed  Google Scholar 

  79. Nicklin SA, Baker AH (2002) Tropism-modified adenoviral and adeno-associated viral vectors for gene therapy. Curr Gene Ther 2:273–293

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Vectorology and Experimental Gene Therapy, University of Rostock, Schillingallee 70, 18057, Rostock, Germany

    Brigitte M. Pützer

  2. Center for Cancer Research and Cancer Therapy, Institute of Molecular Biology, University of Essen Medical School, Hufelandstrasse 55, 45122, Essen, Germany

    Matthias Drosten & Brigitte M. Pützer

Authors
  1. Matthias Drosten
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brigitte M. Pützer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brigitte M. Pützer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Drosten, M., Pützer, B.M. Gene therapeutic approaches for medullary thyroid carcinoma treatment. J Mol Med 81, 411–419 (2003). https://doi.org/10.1007/s00109-003-0455-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-003-0455-6

Keywords

Search

Navigation