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Laryngorhinootologie 2002; 81(7): 509-515
DOI: 10.1055/s-2002-33284
Onkologie
© Georg Thieme Verlag Stuttgart · New York

Antivaskuläre Strategien - ein neues Konzept zur Diagnose und Therapie von Kopf-Hals-Tumoren

Eine ÜbersichtAntivascular Strategies - A New Concept for Diagnosis and Therapy of Head and Neck Cancer. A ReviewM.  Dellian1, 2 , M.  E.  Eichhorn 2 , S.  Strieth 2
  • 1 Klinik und Poliklinik für Hals-, Nasen- und Ohrenkranke der Ludwig-Maximilians-Universität München, Klinikum Großhadern (Direktor: Prof. Dr. med. E. Kastenbauer)
  • 2 Institut für Chirurgische Forschung der Ludwig-Maximilians-Universität München, Klinikum Großhadern (Direktor: Prof. Dr. med. Dr. h. c. mult. K. Meßmer)
Herrn Prof. Dr. med. Ernst Kastenbauer zum 65. Geburtstag gewidmet.
Further Information

Publication History

Eingegangen: 18. Februar 2002

Angenommen: 13. Mai 2002

Publication Date:
12 August 2002 (online)

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Zusammenfassung

Hintergrund: Angiogenese, die Bildung neuer Blutgefäße, ist ein entscheidender Schritt bei der Progression und Metastasierung von Kopf-Hals-Tumoren. Während konventionelle Therapiekonzepte, z. B. Chemotherapie und Bestrahlung, vor allem auf die Tumorzellen selbst abzielen, richtet sich ein antivaskulärer Therapieansatz auf die den Tumor versorgenden Blutgefäße. Antivaskuläre Therapiestrategien können in Anti-Angiogenese und das sog. Vascular Targeting unterteilt werden. Während durch eine antiangiogenetische Therapie die Ausbildung neuer Tumorblutgefäße verhindert werden soll, ist es das Ziel des Vascular Targetings selektiv und effektiv das bereits bestehende Tumorgefäßsystem zu zerstören. Methode: Diese Übersichtsarbeit fasst derzeit bekannte pathophysiologische Mechanismen der Tumorangiogenese und neue Konzepte der antivaskulären Tumortherapie mit besonderem Hinblick auf die mögliche Anwendung zur Behandlung von Tumoren im Kopf-Hals-Bereich zusammen. Ergebnisse: Experimentell kann durch antivaskuläre Strategien eine deutliche Verlangsamung des Tumorwachstums bis hin zu länger anhaltenden Remissionen erzielt werden. Derzeit befinden sich zahlreiche Substanzen in der präklinischen und klinischen Evaluierung, ein Einzug in die klinische Routine ist erst in einigen Jahren zu erwarten. Schlussfolgerungen: Antivaskuläre Strategien sind ein vielversprechendes Konzept zur Behandlung von Kopf-Hals-Karzinomen und deren Metastasen. Ihr Potenzial liegt in der Kombination mit etablierten Therapiemethoden.

Abstract

Background: The development of a blood supply is a crucial step in the progression and metastasis of head and neck cancer. While conventional therapeutic approaches, e. g. chemotherapy and radiation, are focusing on tumor cells, antivascular therapy is directed against the tumor supplying blood vessels. Antivascular treatment can be divided in anti-angiogenesis and vascular targeting. While antiangiogenic therapy prevents neovascularisation by inhibiting new blood vessel growth, the aim of vascular targeting is the destruction of already existing tumor vasculature. Methods: This review will summarise current pathophysiological mechanisms underlying tumor angiogenesis and the concepts of antivascular therapy with respect to possible applications in head and neck cancer. Results: With experimental antivascular strategies a retardation of tumor growth or tumor remission may be achieved, demonstrating proof of principle. At present, numerous drugs are preclinically and clinically evaluated. Conclusions: Antivascular strategies are a promising concept for treatment of patients with head and neck carcinomas. They will most likely exhibit their potential in combination with standard tumor therapies in the future.

Schlüsselwörter

Kopf-Hals-Tumoren - Tumortherapie - Angiogenese - Antiangiogenetische Therapie - Vascular Targeting

Key words

Tumor angiogenesis - Antiangiogenic therapy - Vascular targeting

Literatur

  • 1 Parker S L, Tong T, Bolden S, Wingo P A. Cancer statistics, 1996.  CA Cancer J Clin. 1996;  46 5-27
    PubMedGoogle Scholar
  • 2 Boyle P. Global burden of cancer.  Lancet. 1997;  349 23-26
    CrossrefPubMedGoogle Scholar
  • 3 Forastiere A, Koch W, Trotti A, Sidransky D. Medical progress: head and neck cancer.  N Engl J Med. 2001;  345 1890-1899
    CrossrefPubMedGoogle Scholar
  • 4 Merlano M, Benasso M, Corvo R, Rosso R, Vitale V, Blengio F, Numico G, Margarino G, Bonelli L, Santi L. Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck.  J Natl Cancer Inst. 1996;  88 583-589
    PubMedGoogle Scholar
  • 5 Wendt T G, Grabenbauer G G, Rodel C M, Thiel H J, Aydin H, Rohloff R, Wustrow T P, Iro H, Popella C, Schalhorn A. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study.  J Clin Oncol. 1998;  16 1318-1324
    PubMedGoogle Scholar
  • 6 Folkman J. Tumor angiogenesis: therapeutic implications.  N Engl J Med. 1971;  285 1182-1186
    CrossrefPubMedGoogle Scholar
  • 7 Algire G H, Chalkley H W. Vascular reactions of normal and malignant tissues in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic tissues.  J Natl Cancer Inst. 1945;  6 73-85
    PubMedGoogle Scholar
  • 8 Folkman J. What is the evidence that tumors are angiogenesis dependent?.  J Natl Cancer Inst. 1990;  82 4-6
    CrossrefPubMedGoogle Scholar
  • 9 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease.  Nature Med. 1995;  1 27-31
    CrossrefPubMedGoogle Scholar
  • 10 Holmgren L, O'Reilly M S, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression.  Nat Med. 1995;  1 149-153
    PubMedGoogle Scholar
  • 11 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.  Cell. 1996;  86 353-364
    CrossrefPubMedGoogle Scholar
  • 12 Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.  Nature. 1992;  359 843-845
    CrossrefPubMedGoogle Scholar
  • 13 Kerbel R S, Viloria-Petit A, Klement G, Rak J. ‘Accidental' anti-angiogenic drugs: anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples.  Eur J Cancer. 2000;  36 1248-1257
    CrossrefPubMedGoogle Scholar
  • 14 Riedel F, Hörmann K. Anti-Angiogenese - ein Therapiekonzept zur Behandlung von Kopf-Hals-Karzinomen? Eine Übersicht.  Laryngo-Rhino-Otol. 2001;  80 535-541
    PubMedGoogle Scholar
  • 15 Rak J, Filmus J, Kerbel R S. Reciprocal paracrine interactions between tumor cells and endothelial cells: the ‘angiogenesis progression' hypothesis.  Eur J Cancer. 1996;  32 2438-2450
    CrossrefPubMedGoogle Scholar
  • 16 Fidler I J. Angiogenic heterogeneity: regulation of neoplastic angiogenesis by the organ microenvironment.  J Natl Cancer Inst. 2001;  93 1040-1041
    CrossrefPubMedGoogle Scholar
  • 17 Denekamp J. Endothelial cell proliferation as a novel approach to targeting tumour therapy.  Br J Cancer. 1982;  45 136-139
    PubMedGoogle Scholar
  • 18 Endrich B, Hammersen F, Goetz A, Messmer K. Microcirculatory blood flow, capillary morphology, and local oxygen pressure of the hamster amelanotic melanoma A-Mel-3.  J Natl Cancer Inst. 1982;  68 475-485
    PubMedGoogle Scholar
  • 19 Hammersen F, Osterkamp-Baust U, Endrich B. Ein Beitrag zum Feinbau terminaler Strombahnen und ihrer Entstehung in bösartigen Tumoren. In: Vaupel P, Hammersen F (Hrsg) Mikrozirkulation in malignen Tumoren. Vol 2. Basel; Karger 1983: 15-51
    Google Scholar
  • 20 Gerlowski L E, Jain R K. Microvascular permeability of normal and neoplastic tissues.  Microvasc Res. 1986;  31 288-305
    CrossrefPubMedGoogle Scholar
  • 21 Dvorak H F, Nagy J A, Dvorak T J, Dvorak A M. Identification and characterization of blood vessels in solid tumors that are leaky to circulating macromolecules.  Am J Pathol. 1988;  133 95-109
    PubMedGoogle Scholar
  • 22 Leung D W, Cachianes G, Kuang W J, Goeddel D V, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen.  Science. 1989;  246 1306-1309
    CrossrefPubMedGoogle Scholar
  • 23 Dvorak H F, Brown L F, Detmar M, Dvorak A M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.  Am J Pathol. 1995;  146 1029-1039
    PubMedGoogle Scholar
  • 24 Dvorak A M, Feng D. The vesiculo-vacuolar organelle (VVO). A new endothelial cell permeability organelle.  J Histochem Cytochem. 2001;  49 419-432
    PubMedGoogle Scholar
  • 25 Yancopoulos G D, Davis S, Gale N W, Rudge J S, Wiegand S J, Holash J. Vascular-specific growth factors and blood vessel formation.  Nature. 2000;  407 242-248
    CrossrefPubMedGoogle Scholar
  • 26 Hammersen F, Endrich B, Messmer K. The fine structure of tumor blood vessels. I. Participation of non-endothelial cells in tumor angiogenesis.  Int J Microcirc Clin Exp. 1985;  4 31-43
    PubMedGoogle Scholar
  • 27 Lasic D D. Doxorubicin in sterically stabilized liposomes.  Nature. 1996;  380 561-562
    CrossrefPubMedGoogle Scholar
  • 28 Gokhale P C, Radhakrishnan B, Husain S R, Abernethy D R, Sacher R, Dritschilo A, Rahman A. An improved method of encapsulation of doxorubicin in liposomes: pharmacological, toxicological and therapeutic evaluation.  Br J Cancer. 1996;  74 43-48
    PubMedGoogle Scholar
  • 29 Dellian M, Yuan F, Trubetskoy V S, Torchilin V P, Jain R K. Vascular permeability in a human tumour xenograft: molecular charge dependence.  Br J Cancer. 2000;  82 1513-1518
    CrossrefPubMedGoogle Scholar
  • 30 Thurston G, McLean J W, Rizen M, Baluk P, Haskell A, Murphy T J, Hanahan D, McDonald D M. Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice.  J Clin Invest. 1998;  101 1401-1413
    PubMedGoogle Scholar
  • 31 Tannock I. The relationship between cell proliferation and the vascular system in a transplanted mouse mammary tumour.  Br J Cancer. 1968;  22 258-273
    PubMedGoogle Scholar
  • 32 Hobson B, Denekamp J. Endothelial proliferation in tumours and normal tissues: continuous labelling studies.  Br J Cancer. 1984;  49 405-413
    PubMedGoogle Scholar
  • 33 Denekamp J. Vascular endothelium as the vulnerable element in tumours.  Acta Radiol Oncol. 1984;  23 217-225
    PubMedGoogle Scholar
  • 34 Schnitzer J E. Vascular targeting as a strategy for cancer therapy.  N Engl J Med. 1998;  339 472-474
    CrossrefPubMedGoogle Scholar
  • 35 Eatock M M, Schatzlein A, Kaye S B. Tumour vasculature as a target for anticancer therapy.  Cancer Treat Rev. 2000;  26 191-204
    CrossrefPubMedGoogle Scholar
  • 36 Thomlinson R H, Gray L H. The histological structure of some human lung cancers and the possible implications for radiotherapy.  Br J Cancer. 1955;  9 539-549
    PubMedGoogle Scholar
  • 37 Denekamp J. The tumor microcirculation as a target in cancer therapy: a clearer perspective.  Eur J Clin Invest. 1999;  29 733-736
    CrossrefPubMedGoogle Scholar
  • 38 Denekamp J, Hill S, Hobson B. Vascular occlusion and tumour cell death.  Eur J Cancer Clin Oncol. 1983;  19 271-275
    CrossrefPubMedGoogle Scholar
  • 39 Bloemendal H J, Logtenberg T, Voest E E. New strategies in anti-vascular therapy.  Eur J Clin Invest. 1999;  29 802-809
    CrossrefPubMedGoogle Scholar
  • 40 Dellian M, Abels C, Kuhnle G E, Goetz A E. Effects of photodynamic therapy on leucocyte-endothelium interaction: differences between normal and tumour tissue.  Br J Cancer. 1995;  72 1125-1130
    PubMedGoogle Scholar
  • 41 Arap W, Pasqualini R, Ruoslahti E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model.  Science. 1998;  279 377-380
    CrossrefPubMedGoogle Scholar
  • 42 Denekamp J. Review article: angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy.  Br J Radiol. 1993;  66 181-196
    PubMedGoogle Scholar
  • 43 Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin D J, Bohlen P, Kerbel R S. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity.  J Clin Invest. 2000;  105 15-24
    PubMedGoogle Scholar
  • 44 Dellian M, Walenta S, Gamarra F, Kuhnle G EH, Mueller-Klieser W, Goetz A E. High-energy shock waves enhance hyperthermic response of tumors: effects on blood flow, energy metabolism and tumor growth.  J Natl Cancer Inst. 1994;  86 287-293
    PubMedGoogle Scholar
  • 45 McLean J W, Fox E A, Baluk P, Bolton P B, Haskell A, Pearlman R, Thurston G, Umemoto E Y, McDonald D M. Organ-specific endothelial cell uptake of cationic liposome-DNA complexes in mice.  Am J Physiol. 1997;  273 387-404
    PubMedGoogle Scholar
  • 46 Kong H L, Crystal R G. Gene therapy strategies for tumor antiangiogenesis.  J Natl Cancer Inst. 1998;  90 273-286
    CrossrefPubMedGoogle Scholar
  • 47 Chen Q R, Zhang L, Gasper W, Mixson A J. Targeting tumor angiogenesis with gene therapy.  Mol Genet Metab. 2001;  74 120-127
    CrossrefPubMedGoogle Scholar
  • 48 Sedlacek H H. Pharmacological aspects of targeting cancer gene therapy to endothelial cells.  Crit Rev Oncol Hematol. 2001;  37 169-215
    PubMedGoogle Scholar

Dr. med. Marc Dellian

Klinik und Poliklinik für Hals-, Nasen- und Ohrenkranke · Ludwig-Maximilians-Universität München · Klinikum Großhadern

Marchioninistraße 15 · 81377 München

Email: dellian@icf.med.uni-muenchen.de

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