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Vascular attack as a therapeutic strategy for cancer

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Summary

The blood supply to all solid tumours consists of parasitized normal vessels and new vessels which have been induced to grow by the presence of the tumour. These vessels are inadequate in many respects, being tortuous, thin-walled, chaotically arranged, lacking innervation and with no predetermined direction of flow. The walls consist of a basement membrane lined with rapidly proliferating immature endothelial cells, and are more permeable than normal vessels. The spacing of the vessels and their average diameters are not optimal for nutrient provision.

This paper focuses on the evidence that many existing therapies may already have, as part of their action, a vascular mediated process of killing tumour cells. This may result from local changes within individual vessels or from systemic alterations in blood pressure, viscosity, coagulability etc. The hallmarks of vascular injury are identified and the dangers of discarding useful anticancer agent by failing to understand their mechanism of action are highlighted.

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References

  • Adams GE, Fowler JF, Wardman P (editors): Hypoxic cell sensitizers in radiobiology and radiotherapy. (Proceedings of 8th L.H. Gray Conference.) Brit J Cancer 37: Suppl III 1978

  • Begg AC, Terry NHA: Modification of stromal radiosensitivity by misonidazole and WR-2721. Brit J Radiol 56: 565–570, 1983

    Google Scholar 

  • Belvilacqua MP, Pober NS, Majeau GR, Cotran RS, Gimbrone MA: Interleukin I (IL-I) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells. J Exp Med 160: 618–623, 1984

    Google Scholar 

  • Belvilacqua MP, Pober JS, Majeau GR, Fiers W, Cotran RS, Gimbrone MA: Recombinant tumour necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin I. Proc Nat Acad Sci 83: 4533–4537, 1986

    Google Scholar 

  • Bibby MC, Double JA, Loadman PM, Duke CV: Reduction of tumour blood flow by flavone acetic acid: a possible component of therapy. J Nat Canc Inst 81: 216–220, 1989

    Google Scholar 

  • Bloksma N, Hofhuis F, Benaissa-Trouw B, Willers J: Endotoxin-induced release of tumour necrosis factor and interferonin vivo is inhibited. Cancer Immunol Immunother 14: 41–45, 1982

    Google Scholar 

  • Bugelski PJ, Porter CW, Dougherty TJ: Autoradiographic distribution of hematoporphyrin derivative in normal and tumor tissue of the mouse. Cancer Res 41: 4606–4612, 1981

    Google Scholar 

  • Bujaski A, Nowogrodzka Zagorska M, Lenko J, Miodonski AJ: Angiomorphology of human renal cell carcinoma. Virchows Archiv A. Pathol Anat 415: 103–113, 1989

    Google Scholar 

  • Clauss M, Murray JC, Vianna M, de Waal R, Thurston G, Nawroth P, Gerlag H, Gerlag M, Bach R, Familette P, Stern D: A polypeptide factor produced by fibrosarcoma cells that induces tissue factor and enhances the procoagulant response of endothelium to tumour necrosis factor-cachectin. J Biol Chem (USA) (in press), 1990

  • Denekamp J: Endothelial cell proliferation as a novel approach to targeting tumour therapy. Br J Cancer 45: 136–139, 1982

    Google Scholar 

  • Denekamp J: Endothelial cell attack as a novel approach to cancer therapy. Cancer Topics, Vol 6, No 1: 6–8, 1986a

    Google Scholar 

  • Denekamp J: Cell kinetics and radiation biology. Int J Radiat Biol 49: 357–380, 1986b

    Google Scholar 

  • Denekamp J: Induced vascular collapse in tumours: a way of increasing the therapeutic gain in cancer therapy. Brit J Radiol Report 19: 63–70, 1989

    Google Scholar 

  • Denekamp J, Hill SA: Angiogenic attack as a therapeutic strategy for cancer. Radioth & Oncol. In press, 1990

  • Denekamp J, Hill SA, Hobson B: Vascular occlusion and tumour cell death. Eur J Cancer Clin Oncol 19: 217–275, 1983

    Google Scholar 

  • Denekamp J, Hobson B: Endothelial cell proliferation in experimental tumours. Brit J Cancer 46: 711–720, 1982

    Google Scholar 

  • Denekamp J, Michael BD, Harris SR: Hypoxic cell radiosensitizers: comparative tests of some electron affinic compounds using epidermal cell survivalin vivo. Radiat Res 60: 119–132, 1974

    Google Scholar 

  • Denekamp J, Rojas A: Radioprotectionin vivo: cellular heterogeneity and fractionation. Anticarcinogenesis and Radiation Protection. Ed Cerutti PA, Nygaard OF, Simic MG, Pub Plenum 421–430, 1988

  • Duijvestijn AM, Kerkhove M, Bargatze RF, Butcher EC: Lymphoid tissue- and inflammation-specific endothelial cell differentiation defined by monoclonal antibodies. J Immunol 138: 713–719, 1987

    Google Scholar 

  • Dvorak HF, Gresser I: Microvascular injury in pathogenesis of interferon-induced necrosis of subcutaneous tumours in mice. J Nat Canc Inst 81: 497–502, 1989

    Google Scholar 

  • Egawa J, Ishioka K: Construction of blood vessels of experimental tumours — some considerations on the radioresistancy. Elsevier/North Holland Biomedical Press. Treatment of Radioresistant Cancers. Eds M Abe, K Sakamoto and TL Phillips: 213–227, 1979

  • Endrich B, Hammersen F: Hyperthermia-induced changes on capillary ultrastructure. Int J Microcirc Clin Exp 3: 498, 1984

    Google Scholar 

  • Endrich B, Zweifach BW, Reinhold HS, Intaglietta M: Quantitative studies of microcirculatory function in malignant tissue: Influence of temperature on microvascular hemodynamics during the early growth of the BA1112 rat sarcoma. Int J Radiat Oncol Biol Phys 5: 2021–2030, 1979

    Google Scholar 

  • Evelhoch JL, Bissery M-C, Chabot GG, Simpson NE, McCoy CL, Heibrun LK, Corbett TH: Flavone acetic acid (NSC 347512)-induced modulation of murine tumor physiology monitored byin vivo nuclear magnetic resonance spectroscopy. Cancer Res 48: 4749–4755, 1988

    Google Scholar 

  • Fajardo LF: The complexity of endothelial cells: a review. Am J Clin Path 92: 241–250, 1989

    Google Scholar 

  • Fajardo LF, Schreiber AB, Kelly NI, Hahn GM et al.: Thermal sensitivity of endothelial cells. Radiat Res 103: 276–285, 1985

    Google Scholar 

  • Falanga A, Bolognese Dallessandro AP, Casali B, Roncaglioni MC, Donati MB: Several murine metastasizing tumors possess a cysteine proteinase with cancer procoagulant characteristics. Int J Cancer 39: 774–777, 1987

    Google Scholar 

  • Finlay GJ, Smith GP, Fray LM, Baguley BC: Effect of flavone acetic acid on Lewis Lung carcinoma: evidence for an indirect effect. JNCI 80: 241–245, 1988

    Google Scholar 

  • Folkman JK: Tumor angiogenesis.In: Cancer: a comprehensive treatise, vol 3: 355–388. FBecker (ed) Pub Plenum, New York, 1975

    Google Scholar 

  • Folkman J: Angiogenesis and its inhibitors.In: DeVita VTJr, Hellman S, Rosenberg SA (eds): Important advances in oncology Part 1, pp 42–62. Philadelphia, JB Lippincott 1985

    Google Scholar 

  • Folkman J: How is blood vessel growth regulated in normal and neoplastic tissue. Cancer Res 46: 467–473, 1986

    Google Scholar 

  • Folkman J, Langer R, Linhardt RJ, Haudenschild C, Taylor S: Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. Science 221: 719–725, 1983

    Google Scholar 

  • Gullino PM: Extracellular compartments of solid tumors.In: Cancer: a comprehensive treatise. Vol 3, pp 327–354. Becker FF (ed) Pub Plenum Press, NY 1975

    Google Scholar 

  • Hagemeier H-H, Vollmer E, Goerdt S, Schulze-Osthoff K, Sorg C: A monoclonal antibody reacting with endothelial cells of budding vessels in tumours and inflammatory tissues and non-reactive with normal adult tissues. Int J Cancer 38: 481–488

  • Hahn GM: Hyperthermia and Cancer. Plenum Press, New York, 1982

    Google Scholar 

  • Henderson BW, Waldow SM, Mang TS, Potter WR, Malone PP, Dugherty TJ: Tumor destruction and kinetics of tumor cell death in two experimental mouse tumours following photodynamic therapy. Cancer Res 45: 572–576, 1985

    Google Scholar 

  • Hill SA, Smith KA, Denekamp J: Reduced thermal sensitivity of the vasculature in a slowly growing tumour. Int J Hyperth 5: 359–370, 1989a

    Google Scholar 

  • Hill SA, Williams KB, Denekamp J: Vascular collapse after flavone acetic acid: a possible mechanism of its anti-tumour action. Europ J Cancer Clin Oncol 251: 1419–1424, 1989

    Google Scholar 

  • Hill SA, Williams K, Denekamp J: The anti-tumour activity of flavone acetic acid. Gray Laboratory Annual Report (1989), pp 77–79, 1990a

  • Hill SA, Williams K, Denekamp J: Factors influencing the toxicity of flavone acetic acid in mice. Acta Oncologica (submitted), 1990b

  • Hirst DG, Denekamp J, Hobson B: Proliferation kinetics of endothelial and tumour cells in three mouse mammary carcinomas. Cell Tissue Kinet 15: 251–261, 1982

    Google Scholar 

  • Hodgkiss RJ, Jones G, Long A, Parrick J, Smith KA, Stratford MRL, Wilson GD: Flow cytometric evaluation of hypoxic cells in solid experimental tumours using fluorescence histochemistry. Submitted, 1990

  • Jain RK: Determinants of tumour blood flow: a review. Cancer Res 48: 2641–2658, 1988

    Google Scholar 

  • Jain RK: Delivery of novel therapeutic agents in tumours: physiological barriers and strategies. J Nat Canc Inst, 1989

  • Kalinowski F, Schaefer C, Tyler G, Vaupel P:In vivo targets of recombinant tumour necrosis factor α: blood flow, oxygen consumption and growth of isotransplanted rat tumours. Brit J Cancer 60: 555–560, 1989

    Google Scholar 

  • Kerr DJ, Kaye SB, Cassidy J, Bradley C, Rankin EM, Adams L: Phase I and pharmacokinetic study of flavone acetic acid. Cancer Res 47: 6776–6781, 1987

    Google Scholar 

  • Kotasek D, Vercellotti GM, Ochoa AC, Bach FH, White JG, Jacob HS: Mechanism of cultured endothelial injury induced by lymphokine activated killer cells. Cancer Res 48: 5528–5532, 1988

    Google Scholar 

  • Lee SY, Song CW, Levitt SH: Change in fibrinogen turnover in tumours by hyperthermia. Eur J Cancer Clin Oncol 21: 1507–1513, 1985

    Google Scholar 

  • MacPherson GG, North RJ: Endotoxin mediated necrosis and regression of established tumours in the mouse: a correlative study of quantitative changes in blood flow and ultrastructural morphology. Cancer Immun Immunother 21: 209–216, 1986

    Google Scholar 

  • Moore JV, West CML: Vascular function and tissue injury in murine skin following hyperthermia and photodynamic therapy, alone and in combination. Radiat Res (submitted), 1990

  • Mueller-Klieser W, Vaupel P, Maanz R, Schmidseder R: Intracapillary oxyhemoglobin saturation of malignant tumours in humans. Int J Radiat Oncol Biol Phys 7: 1397–1404, 1981

    Google Scholar 

  • Murray JC, Randhawa VS, Denekamp J: The effects of melphalan and misonidazole on the vasculature of a murine sarcoma. Brit J Cancer 55: 233–238, 1987

    Google Scholar 

  • Murray JC, Smith KA, Lauk S: Vascular markers for murine tumours. Radiotherapy and Oncology 16: 221–234, 1989a

    Google Scholar 

  • Murray JC, Smith KA, Thurston G: Flavone acetic acid induces a coagulopathy in mice. Brit J Cancer 60: 729–733, 1989b

    Google Scholar 

  • Murray JC, Clauss M, Denekamp J, Stern D: Selective induction of endothelial cell tissue factor in the presence of a tumor-derived mediator: a potential mechanism of flavone acetic acid action in tumour vasculature. In preparation, 1990

  • Nawroth P, Handley D, Matsueda G, deWaal R, Gerlach H, Blohm D, Stern D: Tumour necrosis factor/cachectin-induced intravascular fibrin formation in Meth-A fibrosarcoma. J Exp Med 168: 637–648, 1988

    Google Scholar 

  • Peterson HI (ed): Tumor blood circulation. Pub CRC Press Inc Boca Raton Florida, 1978

    Google Scholar 

  • Pober JS, Bevilacqua MP, Mendrick DL, Lapierre LA, Fiers W, Gimbrone MA: Two distinct monokines, interleukin I and tumour necrosis factor. Each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J Immunol 136: 1680, 1986

    Google Scholar 

  • Randhawa VS, Stewart FA, Denekamp J, Stratford MRLS: Factors influencing the chemosensitization of melphalan by misonidazole. Brit J Cancer 51: 219–228, 1984

    Google Scholar 

  • Rappaport DS, Song CW: Blood flow and intravascular volume of mammary adenocarcinoma and normal tissues of rat during and following hyperthermia. Int J Radiat Oncol Biol Phys 9: 539–547, 1983

    Google Scholar 

  • Reinhold HS, Visser JWM:In vivo fluorescence of endothelial cell nuclei stained with the dye Bis-benzamide H33342. Int J Microcirc Clin Exp 2: 143, 1983

    Google Scholar 

  • Reinhold HS, Blachiewiczz B, Van denBerg-Blok AE: Decrease in tumour microcirculation during hyperthermia.In: Cancer Therapy by Hyperthermia and Radiation, pp 231–232. Streffer C, VanBeuningen D, Dietzel F, Rottinger E, Robinson JE, Scherrer E, Seeber S, Trott KR (eds). Urban and Schwarzenberg, Baltimore and Munich, 1978

    Google Scholar 

  • Ryan JW, Ryan US: Endothelial surface enzymes and the dynamic processing of plasma substrates. Int Rev Exp Pathol 26: 1–43, 1984

    Google Scholar 

  • Schlingemann RO, Dingjan GM, Emeis JJ, Block J, Warnaar SO, Ruiter DJ: Monoclonal antibody PAL-E specific for endothelium. Lab Invest 52: 71–76, 1985

    Google Scholar 

  • Selman SH, Kreimer-Birnbaum M, Klaunig JE, Goldblatt PJ, Keck RW, Britton SL: Blood flow in transplantable bladder tumours treated with hematoporphyrin derivative and light. Cancer Res 44: 1924–1927, 1984

    Google Scholar 

  • Sidky YA, Borden EC: Inhibition of angiogenesis by interferons: effects on tumor- and lymphocyte-induced vascular responses. Cancer Res 47: 5155–5161, 1987

    Google Scholar 

  • Smith GP, Calveley SB, Smith MJ, Baguley BC: Flavone acetic zcid (NSC347512) induced haemorrhagic necrosis of mouse colon 26 and 38 tumours. Eur J Cancer Clin Oncol 23: 1209–1211, 1988

    Google Scholar 

  • Smith KA, Thurston G, Denekamp J: Studies on the mechanism of action of FAA: effects of tumour clamping. Gray Laboratory Annual Report (1989) 67, 1990

  • Solesvik OV, Rofstad EK, Brustad T: Vascular changes in a human malignant melanoma xenograft following single-dose irredlation. Radiation Research 98: 115–128, 1984

    Google Scholar 

  • Song CW: Effect of local hyperthermia on blood flow and microenvironment: a review. Cancer Res 44: 4721–4730, 1984

    Google Scholar 

  • Song CW: Role of blood flow in hyperthermia.In: Hyperthermia and Oncology, Vol 3. Urano M, Douple EB (eds) VNA Scientific (Netherlands), in press, 1990

    Google Scholar 

  • Star WM, Marijnissen HPA, Van denBerg Block AE, Versteeg JAC, Franken KAP, Reinhold HS: Destruction of rat mammary tumor and normal tissue microcirculation by hematoporphyrin derivative photoradiation observedin vivo in sandwich observation chambers. Cancer Res 46: 2532–2540, 1986

    Google Scholar 

  • Stephens TC, Peacock JH: Cell yield and cell survival following chemotherapy of the B16 melanoma. Br J Cancer 38: 591–598, 1978

    Google Scholar 

  • Stern D, Nawroth P, Handley D, Kisiel W: An endothelial cell-dependent pathway of coagulation. Proc Natl Acad Sci 82: 2523–2427, 1985

    Google Scholar 

  • Sutherland RM: Selective chemotherapy of non-cycling in anin vitro tumour model. Cancer Res 34: 3501–3503, 1974

    Google Scholar 

  • Thomlinson RH, Craddock EA: The gross response of an experimental tumour to single doses of X-rays. Br J Cancer 21: 108–125, 1967

    Google Scholar 

  • Thomlinson RH, Gray LH: The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9: 539–547, 1955

    Google Scholar 

  • Thurston G, Smith KA, Murray JC: The effect of flavone acetic acid on coagulation and permeability in experimental tumours. Brit J Radiol. In press, 1990

  • Vaupel PW, Frinak S, Bicher HI: Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Research 41: 2008–2013, 1981

    Google Scholar 

  • Ward JF: Mechanisms of DNA repair and their potential modification for radiotherapy. Int J Radiat Oncol Biol Phys 12: 1027–1032, 1986

    Google Scholar 

  • Weiss RB, Greene RF, Knight RD, 4 others: Phase I and clinical pharmacology study of intravenous flavone acetic acid (NSC347512). Cancer Res 48: 5878, 1988

    Google Scholar 

  • Williams K, Joiner B, Hill SA: FAA effects on mice bearing skin wounds or implanted sponges. Gray Laboratory Annual Report (1989), p 76–78, 1990

  • Wong TW, Whitmore GF, Gulyas S: Studies on the toxicity and radiosensitizing ability of misonidazole under conditions of prolonged incubation. Radiat Res 75: 541–555, 1978

    Google Scholar 

  • Yuhas JM, Yurconic M, Kligerman MM, Peterson DF: Combined use of radioprotective and radiosensitizing drugs in experimental radiotherapy. Radiat Res 70: 433–443, 1977

    Google Scholar 

  • Yuhas JM, Storer JB: Differential chemoprotection of normal and malignant tissues. J Natl Cancer Inst 42: 331–335, 1969

    Google Scholar 

  • Yuhas JM: Active versus passive absorption kinetics as the basis for selective protection of normal tissues by S-2-(3-Aminopropylanino)-ethylphosphorothioic acid. Cancer Res 40: 1519–1524, 1980

    Google Scholar 

  • Zacharski LR, Memoli VA, Rousseau SM, Kisiel W: Occurrence of blood coagulation factorsin situ in small cell carcinoma of the lung. Cancer 60: 2675–2681, 1987

    Google Scholar 

  • Zwi LJ, Baguley BC, Gavin JB, Wilson WR: The use of vascularised spheroids to investigate the action of flavone acetic acid on tumour blood vessels. Brit J Cancer, in press, 1990

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  1. CRC Gray Laboratory, Mount Vernon Hospital, P.O. Box 100, HA6 2JR, Northwood, Middlesex, UK

    Juliana Denekamp

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Denekamp, J. Vascular attack as a therapeutic strategy for cancer. Cancer Metast Rev 9, 267–282 (1990). https://doi.org/10.1007/BF00046365

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