Angiogenesis pp 193-207 | Cite as

Therapeutic Angiogenesis in Surgery and Oncology

  • Michael Höckel
  • Karlheinz Schlenger
  • Renate Frischmann-Berger
  • Sabine Berger
  • Peter Vaupel
Part of the NATO ASI Series book series (NSSA, volume 263)


The aim of this presentation is to demonstrate the pathological importance of microenvironmental tissue hypoxia and to elucidate a general treatment concept for this situation which we have termed therapeutic angiogenesis 1. Hypoxia not only represents an insufficient oxygen supply for the cells of a given tissue area but is also regarded as an indicator for their metabolic deprivation and the concomitant accumulation of waste products. Therapeutic angiogenesis applied either with clinically established methods or using novel ways, which are the objectives of laboratory research and clinical trials at present, or in so far hypothetical forms, should lead to an expansion of the functional microvascular space resulting in an increased nutritive blood flow. Thus microregional oxygen availability should be elevated and directly counteract local tissue hypoxia. The problems of nutritional deprivation and waste product accumulation are also treated by therapeutic angiogenesis.


Muscle Flap Therapeutic Angiogenesis Pelvic Wall Surgical Debulking Chronic Venous Insufficiency 
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.
    Höckel, M., Schienger, K., Doctrow, S., Kissel, T., and Vaupel, P. Therapeutic angiogenesis. Arch. Surg., 128: 423–429, 1993.PubMedCrossRefGoogle Scholar
  2. 2.
    Jonsson, K., Jensen, J.A., Goodson, W.H., and Hunt, T.K. Wound healing in subcutaneous tissue of surgical patients in relation to oxygen availability Surg. Fonnn, 37: 86–88, 1986.Google Scholar
  3. 3.
    Hunt, T.K., and Pai, M.P. The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis. Surg. Gynecol. Obstet., 135: 561–567, 1972.PubMedGoogle Scholar
  4. 4.
    Pai, M.P., and Hunt, T.K. Effect of varying oxygen tensions on healing of open wounds. Surg. Gynecol. Obstet., 135: 756–758, 1972.PubMedGoogle Scholar
  5. 5.
    Jonsson, K., Hunt, T.K., and Mathes, S.J. Effect of environmental oxygen on bacterial induced tissue necrosis in flaps. Surg. Forum, 35: 589–591, 1984.Google Scholar
  6. 6.
    Knighton, D.R., Halliday, B., and Hunt, T.K. Oxygen as an antibiotic: The effect of inspired oxygen on infection. Arch. Surg., 119: 199–204, 1984.PubMedCrossRefGoogle Scholar
  7. 7.
    Brown, J.M. Tumor hypoxia, drug resistance, and metastases. J. Natl. Cancer Inst., 82: 338–339, 1990.PubMedCrossRefGoogle Scholar
  8. 8.
    Coleman, C.N. Hypoxia in tumors: a paradigm for the approach to biochemical and physiologic heterogeneity. J. Natl. Cancer Inst., 80: 310–317, 1988.PubMedCrossRefGoogle Scholar
  9. 9.
    Moulder, J.E., and Rockwell, S. Hypoxic fractions of solid tumors: experimental techniques, methods of analysis, and a survey of existing data. IN. J. Radial. Oncol. Biol. Phys., 10. 695–712, 1984.CrossRefGoogle Scholar
  10. 10.
    Powers, W.E., and Tolmach, L.J. A multicomponent X-ray survival curve for mouse lymphosarcoma cells irradiated in vivo. Nature, 197: 710–711, 1963.PubMedCrossRefGoogle Scholar
  11. 11.
    Rice, G.C., Hoy, C., and Schimke, R.T. Transient hypoxia enhances the frequency of dihydrofolate reductase gene amplification in chinese hamster ovary cells. Proc. Natl. Acad. Sci. USA, 83: 5978–5982, 1986.PubMedCrossRefGoogle Scholar
  12. 12.
    Teicher, B.A., Holden, S.A., Al-Achi, A., and Herman, T.S. Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaIIC murine fibrosarcoma. Cancer Res., 50: 3339–3344, 1990.PubMedGoogle Scholar
  13. 13.
    Gerweck, L.E., Nygaard, T.G., and Burlett, M. Response of cells to hyperthermia under acute and chronic hypoxic conditions. Cancer Res., 39: 966–972, 1979.PubMedGoogle Scholar
  14. 14.
    Overgaard, J. Effect of hyperthermia on the hypoxic fraction in an experimental mammary carcinoma in vivo. Br. J. Radiol., 54: 245–249, 1981.PubMedCrossRefGoogle Scholar
  15. 15.
    Chapman, J.D. The detection and measurement of hypoxic cells in solid tumors. Cancer, 54: 2441–2449, 1984.PubMedCrossRefGoogle Scholar
  16. 16.
    Gray, L.H., Conger, A.D., Ebert, M., Homsey, S., and Scott, O.C.A. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br. J. Radiol., 26: 638–648, 1953.PubMedCrossRefGoogle Scholar
  17. 17.
    Drescher, E.E., and Gray, L.H. Influence of oxygen tension on X-ray induced damage in Ehrlich ascites tumor cells irradiated in vitro and in vivo. Radiol. Res., 11: 115–146, 1959.CrossRefGoogle Scholar
  18. 18.
    Durand, R.E. Keynote address: The influence of microenvironmental factors on the activity of radiation and drugs. Int. J. Rad. One. Biol. Phys., 20: 253–258, 1991.CrossRefGoogle Scholar
  19. 19.
    Young, S.D., Marshall, R.S., and Hill, R.P. Hypoxia induces DNA oveiueplication and enhances metastatic potential of murine tumor cells. Proc. Natl. Acad. Sci., 85: 9533–9537, 1988.PubMedCrossRefGoogle Scholar
  20. 20.
    Höckel, M., Schienger, K., Knoop, C., and Vaupel, P. Oxygenation of carcinomas of the uterine cervix: Evaluation by computerized 02 tension measurements. Cancer Res., 51: 6098–6102, 1991.PubMedGoogle Scholar
  21. 21.
    Höckel, M., Knoop, C., Schienger, K., Vomdran, B., Baußmann, E., Mitze, M., Knapstein, P.G., and Vaupel, P. Intratumoral p02 predicts survival in advanced cancer of the uterine cervix. Radiotherapy and Oncology, 26: 45–50, 1993.PubMedCrossRefGoogle Scholar
  22. 22.
    Hoshino, S., Hamada, O., Iwaya, F., Takahira, H., and Honda, K. Omental transplantation for chronic occlusive arterial diseases. Int. Surg., 64: 21–29, 1979.PubMedGoogle Scholar
  23. 23.
    Goldsmith, H.S. Salvage of end stage ischemic extremities by intact omentum. Surgery, 88: 732–736, 1980.PubMedGoogle Scholar
  24. 24.
    Hoshino, S., Nakayama, K., Igari, T., and Honda, K. Long-term results of omental transplantation for chronic occlusive arterial diseases. Int. Surg., 68: 47–50, 1983.PubMedGoogle Scholar
  25. 25.
    In: “The Greater Omentum,” Liebermann-Meffert, D.; White, H.,ed., Springer, Berlin (1983).Google Scholar
  26. 26.
    Maurya, S.D., Singhal, S., Gupta, H.C., Elhence, I.P., and Sharma, B D Pedicled omental grafts in the revascularization of ischemic lower limbs in Buerger’s disease. Int. Surg., 70: 253–255, 1985.PubMedGoogle Scholar
  27. 27.
    Pevec, W.C., Hendricks, D., Rosenthal, M.S., Shestak, K.C., Steed, D.L., and Webster, M.W. Revascularization of an ischemic limb by use of a muscle pedicle flap: A rabbit model. J. Vasc. Surg., 13: 385–390, 1991.PubMedCrossRefGoogle Scholar
  28. 28.
    Mathes, N. Classification of the vascular anatomy of muscles: Experimental and clinical correlation. Plast. Reconstr. Surg., 67: 177–187, 1981.Google Scholar
  29. 29.
    Nottebeart, M., Lane, J.M., Juhn, A., Burstein, A., Schneider, R., Klein, C., Sinn, R.S., Dowling, C., Cornell, C., and Catsimpoolas, N. Omental angiogenic lipid fraction and bone repair. An experimental study in the rat. J. Orthop. Res., 7: 157–169, 1989.CrossRefGoogle Scholar
  30. 30.
    Anthony, J.P., Mathes, S.J., and Alpert, B.S. The muscle flap in the treatment of chronic lower extremity osteomyelitis: Results in patients over 5 years after treatment. Plast. Reconstr. Surg., 88: 311 1991.PubMedCrossRefGoogle Scholar
  31. 31.
    Jones, N.F., Eadie, P., Johnson, P.C., and Mears, D.C. Treatment of chronic infected hip arthroplasty wounds by radical debridement and obliteration with pedicled and free muscle flaps. Plast. Reconstr. Surg., 88: 95 1991.PubMedCrossRefGoogle Scholar
  32. 32.
    Phillips, G.D., and Knighton, D.R. Angiogenic activity in damaged skeletal muscle (43025). P.S.E.B.M., 193: 197–202, 1990.Google Scholar
  33. 33.
    Green, H., Kehinde, O., and Thomas, J. Growth of cultured human epidermal cells into multiple epithelia suitable for grafting. Proc. Natl. Acad. Sci. USA, 76: 5665–5668, 1979.PubMedCrossRefGoogle Scholar
  34. 34.
    Romagnoli, G., De Luca, M., Faranda, F., Bandelloni, R., Franzi, A.T., Cataliotti, F., and Cancedda, R. Treatment of posterior hypospadias by the autologous graft of cultured urethral epithelium. N. Engl. J. Med., 323: 527–530, 1990.PubMedCrossRefGoogle Scholar
  35. 35.
    Eisenstein, R. Angiogenesis in arteries: Review. Phannac. Ther., 49: 1–19, 1991.Google Scholar
  36. 36.
    Odedra, R., and Weiss, J.B. Low molecular weight angiogenesis factors. Phannac. Ther., 49: 111–124, 1991.CrossRefGoogle Scholar
  37. 37.
    Lynch, S.E., Colvin, R.B., and Antoniades, H.N. Growth factors in wound healing. Single and synergistic effects on partial thickness porcine wounds. J. Clin. Invest., 84: 640–646, 1989.PubMedCrossRefGoogle Scholar
  38. 38.
    Laato, M., Niinikoski, J., Lebel, L., and Gerdin, B. Stimulation of wound healing by epidermal growth factor (EGF): A dose dependent effect. Ann. Surg., 203: 379–381, 1986.PubMedCrossRefGoogle Scholar
  39. 39.
    Buckley, A., Davidson, J.M., Kamerath, C.D., and Woodward, S.C. Epidermal growth factor increases granulation tissue formation dose dependently. J. Surg. Res., 43: 322–328, 1987.PubMedCrossRefGoogle Scholar
  40. 40.
    Broadley, K.N., Aquino, A.M., and Hicks, B. Growth factors -FGF and TGF-betaaccelerate the rate of wound repair in normal and in diabetic rats. Int. J. Tiss. Reac., 10: 345–353, 1988.Google Scholar
  41. 41.
    Brown, G.L., Curtsinger, L.J., White, M., Mitchell, R.D., Pietsch, J., Nordquist, R., von Fraunhofer, A., and Schultz, G.S. Acceleration of tensile strength of incisions treated with EGF and TGF-beta. Ann. Surg., 208: 788–794, 1988.PubMedCrossRefGoogle Scholar
  42. 42.
    Brown, G.L., Nanney, L.B., Griffen, J., Cramer, A.B., Yancey, J.M., Curtsinger L.J., Holtzin, L., Schultz, G.S., Jurkiewicz, M.J., and Lynch, J.B. Enhancement of wound healing by topical treatment with epidermal growth factor. N. Engl. J. Med., 321: 76–79, 1989.PubMedCrossRefGoogle Scholar
  43. 43.
    Langer, R., and Moses, M. Biocompatible controlled release polymers for delivery of polypeptides and growth factors. J. Cell. Biochem., 45: 340–345, 199LGoogle Scholar
  44. 44.
    Chu, G.H., Ogawa, Y., and McPherson, J.M. Collagen wound healing matrices and process for their production. Collagen Corp. 990; WO 90/00060.Google Scholar
  45. 45.
    Kopecek, J., and Ulbrich, K. Biodegradation of biomedical polymers. Prog. Polym. Sci., 9: 1–58, 1983.CrossRefGoogle Scholar
  46. 46.
    Höckel, M., Ott, S., Siemann, U., and Kissel, T. Prevention of peritoneal adhesions in the rat with sustained intraperitoneal dexamethasone delivered by a novel therapeutic system. Ann. Chirurg. Gynaecol., 76: 306–313, 1987.Google Scholar
  47. 47.
    In: “Novel drug delivery,” Prescott, L.F.; Nimmo, W.S.,ed., Wiley and Sons, Chichester (UK ) (1989).Google Scholar
  48. 48.
    Kissel, T., Brich, Z., Bantle, S., Lancranjan, I., Nimmerfall, F., and Vit, P. Parenteral depot systems on the basis of biodegradable polyesters. J. Contr. Rel.,in press.Google Scholar
  49. 49.
    Edington, H.D., Sugarbaker, P.H., and McDonald, H.D. Management of the surgically traumatized, irradiated, and infected pelvis. Surgery, 103: 690–697, 1987.Google Scholar
  50. 50.
    Mathes, S. J., Feng, L.J., and Hunt, T. Coverage of the infected wound. Ann. Surg., 198: 420–426, 1983.PubMedCrossRefGoogle Scholar
  51. 51.
    Eshima, I., Mathes, S.J., and Paty, P. Comparison of the intracellular bacterial killing activity of leukocytes in musculocutaneous and random-pattern flaps. Plast. Reconstr. Surg., 86: 541–547, 1990.PubMedCrossRefGoogle Scholar
  52. 52.
    Knighton, D.R., Ciresi, K.F., Fiegel, B.S., Austin, L.L., and Butler, E.L. Classification and treatment of chronic nonhealing wounds. Ann. Surg., 204: 322–330, 1986.PubMedCrossRefGoogle Scholar
  53. 53.
    Burgos, H., Herd, A., and Bennett, J.P. Placental angiogenic and growth factors in the treatment of chronic varicose ulcers: preliminary communication. J. Royal Soc. Med., 82: 598–599, 1989.Google Scholar
  54. 54.
    Knighton, D.R., Ciresi, K.F., Fiegel, V.D., Schumerth, S., Butler, E., and Cerra, F. Stimulation of repair in chronic, nonhealing, cutaneous ulcers using platelet derived wound healing formula. Surg., Gynecol. and Obstet. 170:: 56–60, 1990.Google Scholar
  55. 55.
    Hase, S., Nakazawa, S., Tsukamoto, Y., and Segawa, K. Effects of prednisolone and human epidermal growth factor on angiogenesis in granulation tissue of gastric ulcer induced by acetic acid. Digestion, 42: 135–142, 1989.PubMedCrossRefGoogle Scholar
  56. 56.
    Folkman, J., Szabo, S., Stovroff, M., McNeil, P., Li, W., and Shing, Y. Duodenal ulcer. Discovery of a new mechanism and development of angiogenic therapy that accelerates healing. Ann. Surg., 214: 414–427, 1991.PubMedCrossRefGoogle Scholar
  57. 57.
    tenDijke, P., and Iwata, K.K. Growth factors for wound healing. Biol. Technology, 7: 793–798, 1989.CrossRefGoogle Scholar
  58. 58.
    Unger, E.F., Sheffield, C.D., and Epstein, S.E. Creation of anastomoses between an extracardiac artery and the coronary circulation. Proof that myocardial angiogenesis occurs and can provide nutritional blood flow to the myocardium. Circulation, 82: 1449–1466, 1990.PubMedCrossRefGoogle Scholar
  59. 59.
    Myers, B. Understanding flap necrosis. Plast. Reconstr. Surg., 77: 813–814, 1986.Google Scholar
  60. 60.
    Heckel, M., and Burke, J.F. Angiotropin treatment prevents flap necrosis and enhances dermal regeneration in rabbits. Arch. Surg., 124: 693–698, 1989.CrossRefGoogle Scholar
  61. 61.
    McGregor, I.A., and Morgan, G. Axial and random pattern flaps. Br. J. Plast. Surg., 26: 202–213, 1973.PubMedCrossRefGoogle Scholar
  62. 62.
    in: “The Arterial Anatomy of Skin Flaps,” Cormack, G.C.; Lamberty, B.G.H.,ed., Churchill Livingstone, New York (1986).Google Scholar
  63. 63.
    Eppley, B.L., Connolly, D.T., Winkelmann, T., Sadove, A.M., Heuvelman, D., and Feder, J. Free bone graft reconstruction of irradiated facial tissue: Experimental effects of basic fibroblast growth factor stimulation. Plast. Reconstr. Surg., 88: 1, 1991.PubMedCrossRefGoogle Scholar
  64. 64.
    Penkert, G., Bini, W., and Samii, M. Revascularization of nerve grafts: An experimental study. J. Reconstr. Microsurg., 4: 319–325, 1988.PubMedCrossRefGoogle Scholar
  65. 65.
    Ohta, H., Ishiyama, J., Saito, H., and Nishiyama, N. Effects of pretreatment with basic fibroblast growth factor, epidermal growth factor and nerve growth factor on neuron survival and neovascularization of superior cervical ganglion transplanted into the third ventricle in rats. Japan. J. Phannacol., 55: 255–262, 1991.CrossRefGoogle Scholar
  66. 66.
    Cordeiro, P.G., Seckel, B.R., Lipton, S.A., D’Amore, P.A., Wagner, J., and Madison, R. Acidic fibroblast growth factor enhances peripheral nerve regeneration in vivo. Plast. Reconstr. Surg., 83: 1013–1019, 1989.PubMedCrossRefGoogle Scholar
  67. 67.
    Lyons, M.K., Anderson, R.E., and Meyer, F.B. Basic fibroblast growth factor promotes in vivo cerebral angiogenesis in chronic forebrain ischemia. Brain Res., 558: 315–320, 1991.PubMedCrossRefGoogle Scholar
  68. 68.
    Lawrence, T.W., Sporn, M.B., Gorschboth, C., Norton, J.A., and Grotendorst, G.R. The reversal of an adriamycin induced healing impairment with chemoattractants and growth factors. Ann. Surg., 203: 142–147, 1986.PubMedCrossRefGoogle Scholar
  69. 69.
    Mooney, D.P., Gamelli, R.L., and O’Reilly, M. Improved wound healing through the local delivery of tumor necrosis factor. Surg. Forum, 39: 77–79, 1988.Google Scholar
  70. 70.
    Curtsinger, L.J., Pietsch, J.D., Brown, G.L., von Fraunhofer, A., Ackerman, D., Polk, H.C. J., and Schultz, G.S. Reversal of adriamycin-impaired wound healing by transforming growth factor-beta. Surg. Gynecol. Obstet., 168: 517–522, 1989.PubMedGoogle Scholar
  71. 71.
    Latoo, M., Jyrki, H., Veli, M.K., Niinikkoski, J., and Gerdin, B. Epidermal growth factor (EGF) prevents methylprednisolone induced inhibition of wound healing. J. Surg. Res., 47: 354–359, 1989.CrossRefGoogle Scholar
  72. 72.
    Eliseenko, V.I., Skobelkin, O.K., Chegin, V.M., and Degtyarev, M.K. Microcirculation and angiogenesis during wound healing by first and second intention. Bull. Exp. Biol. Med., 105: 289–292, 1988.CrossRefGoogle Scholar
  73. 73.
    Schienger, K., Höckel, M., Schwab, R., and Frischmann-Berger, R. How to improve the uterotomy healing. I Effects of fibrin and tumor necrosis factor alpha in the rat uterotomy model. J. Surg. Res., in press Google Scholar
  74. 74.
    Greisler, H.P., Klosak, J.J., Dennis, J.W., Karesh, S.M., Ellinger, J., and Kim, D.U. Biomaterial pretreatment with ECGF to augment endothelial cell proliferation. J. Vasc. Surg., 5: 393–402, 1987.PubMedGoogle Scholar
  75. 75.
    Clowes, A.W., and Kohler, T. Graft endothelialization: The role of angiogenic mechanisms. J. Vasc. Surg., 13: 734–736, 1991.PubMedCrossRefGoogle Scholar
  76. 76.
    Buntrock, P., Jentzsch, K.D., and Heder, G. Stimulation of wound healing, using brain extract with fibroblast growth factor (FGF) activity. Exptl. Path., 21: 46–53, 1982.CrossRefGoogle Scholar
  77. 77.
    Buckley, A., Davidson, J.M., Kamerath, C.D., Wolt, T.B., and Woodward, S.C. Sustained release of epidermal growth factor accelerates wound repair. Proc. Natl. Acad. Sci. USA, 82: 7340–7344, 1985.PubMedCrossRefGoogle Scholar
  78. 78.
    Winet, H., Bao, J.Y., and Moffat, R. A control model for tibial cortex neovascularization in the bone chamber. J. Bone Mineral Res., 5: 19–30, 1990.CrossRefGoogle Scholar
  79. 79.
    Gills, J.P., and McIntyre, L.G. Growth factors and their promising future. J. Amer. Optom. Assoc., 60: 442–445, 1989.Google Scholar
  80. 80.
    Woost, P.G., Brightwell, J., Eiferman, A., and Schultz, G. Effect of growth factors with dexamethasone on healing of rabbit corneal stromal incisions. Exptl. Eye Res., 40: 47–60, 1985.CrossRefGoogle Scholar
  81. 81.
    Schultz, G.S., White, M., Mitchell, R., Brown, G., Lynch, J., Twardzik, D.R., and Todaro, G.J. Epithelial wound healing enhanced by transforming growth factor alpha and vaccinia growth factor. Science, 235: 350–352, 1987.PubMedCrossRefGoogle Scholar
  82. 82.
    Nanny, L.B. Epidermal and dermal effects of epidermal growth factor during wound repair. J. Invest. Dennatol., 94: 624–629, 1990.CrossRefGoogle Scholar
  83. 83.
    Hoskins, W., and Rubin, S. Surgery in the treatment of patients with advanced ovarian cancer. Semin. OncoL, 18: 213–221, 1991.PubMedGoogle Scholar
  84. 84.
    Simpson-Herren, L., Sanford, A.H., and Holmquist, J.P. Effects of surgery on the cell kinetics of residual tumor. Cancer Treat. Rep., 60: 1749–1760, 1976.PubMedGoogle Scholar
  85. 85.
    Gunduz, N., Fisher, B., and Saffer, E.A. Effect of surgical removal on the growth and kinetics of residual tumor. Cancer Res., 39: 3861–3865, 1979.PubMedGoogle Scholar
  86. 86.
    Wong, R.J., and DeCosse, J.J. Cytoreductive surgery. Gynecol. and Obstet., 170: 279–281, 1990.Google Scholar
  87. 87.
    Höckel, M., Knapstein, P.G., and Kutzner, J. A novel combined operative and radiotherapeutic treatment approach for recurrent gynecologic malignant lesions infiltrating the pelvic wall. Surg., Gynecol. and Obstet., 173: 297–302, 1991.Google Scholar
  88. 88.
    Höckel, M., and Knapstein, P.G. The combined operative and radiotherapeutic treatment (CORI) of recurrent tumors infiltrating the pelvic wall: First experience with 18 patients. GynecoL Oncol., 46. 20–28, 1992.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Michael Höckel
    • 1
  • Karlheinz Schlenger
    • 1
  • Renate Frischmann-Berger
    • 1
  • Sabine Berger
    • 1
  • Peter Vaupel
    • 2
  1. 1.Department of Obstetrics and GynecologyUniversity of Mainz Medical CenterMainzGermany
  2. 2.Institute of Physiology and PathophysiologyUniversity of Mainz Medical CenterMainzGermany

Personalised recommendations