Abstract
The anti-vascular action of the tubulin binding agent combretastatin A-4 phosphate (CA-4-P) has been quantified in two types of murine tumour, the breast adenocarcinoma CaNT and the round cell sarcoma SaS. The functional vascular volume, assessed using a fluorescent carbocyanine dye, was significantly reduced at 18 h after CA-4-P treatment in both tumour types, although the degree of reduction was very different in the two tumours. The SaS tumour, which has a higher nitric oxide synthase (NOS) activity than the CaNT tumour, showed ~10-fold greater resistance to vascular damage by CA-4-P. This is consistent with our previous findings, which showed that NO exerts a protective action against this drug. Simultaneous administration of CA-4-P with a NOS inhibitor, Nω-nitro-L-arginine (L-NNA), resulted in enhanced vascular damage and cytotoxicity in both tumour types. Administration of diethylamine NO, an NO donor, conferred protection against the vascular damaging effects. Following treatment with CA-4-P, neutrophil infiltration into the tumours, measured by myeloperoxidase (MPO) activity, was significantly increased. Levels of MPO activity also correlated with the levels of vascular injury and cytotoxicity measured in both tumour types. Neutrophilic MPO generates free radicals and may therefore contribute to the vascular damage associated with CA-4-P treatment. MPO activity was significantly increased in the presence of L-NNA, suggesting that the protective effect of NO against CA-4-P-induced vascular injury may be, at least partially, mediated by limiting neutrophil infiltration. The data are consistent with the hypothesis that neutrophil action contributes to vascular injury by CA-4-P and that NO generation acts to protect the tumour vasculature against CA4-P-induced injury. The protective effect of NO is probably associated with an anti-neutrophil action. © 2000 Cancer Research Campaign
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References
Anderson RF, Patel KB, Reghebi K and Hill SA (1989) Conversion of xanthine dehydrogenase to xanthine oxidase as a possible marker for hypoxia in tumours and normal tissues. Br J Cancer 60: 193–197
Chalkley HW (1943) Method for the quantitative morphologic analysis of tissues. J Natl Cancer Inst 4: 47
Chaplin DJ, Petit GR, Parkins CS and Hill SA (1996) Antivascular approaches to solid tumour therapy: evaluation of tubulin binding agents. Br J Cancer 74: S86–S88
Chaplin DJ, Petit GR and Hill SA (1999) Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate. Anticancer Res 19: 189–196
Dark GG, Hill SA, Prise VE, Tozer GM, Petit GR and Chaplin DJ (1997) Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Res 57: 1829–1834
Eiserich JP, Cross CE, Jones AD, Halliwell B and van der Vleit A (1996) Formation of nitrating and chlorinating species by reaction of nitrite with hypochlorous acid. J Biol Chem 271: 19199–19208
Eiserich JP, Hristova M, Cross SE, Jones AD, Freeman BA, Halliwell B and van der Vleit A (1998) Formation of nitric oxide derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 391: 393–397
Eiserich JP, Estevez AG, Bamburg TV, Ye YZ, Chumley PH, Beckman JS and Freeman BA (1999) Microtubule dysfunction by post-translational nitrotyrosination of α-tubulin; A nitric oxide-dependent mechanism of cellular injury. Proc Natl Acad Sci USA 96: 6365–6370
Folkman J (1990) What is the evidence that tumors are angiogenic dependent?. J Natl Cancer Inst 82: 4–6
Grisham MB, Hernandez LA and Granger DN (1986) Xanthine oxidase and neutrophil infiltration in intestinal ischaemia. Am J Physiol 251: G567–574
Grosios K, Holwell SE, McGown AT, Pettit GR and Bibby MC (1999) In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug. Br J Cancer 81: 1318–1327
Hill SA, Sampson LE and Chaplin DJ (1995) Antivascular approaches to solid tumour therapy: Evaluation of vinblastine and flavone acetic acid. Int J Cancer 63: 119–123
Horsman MR, Ehrnrooth E, Ladekarl M and Overgaard J (1998) The effect of combretastatin A-4 disodium phosphate in a C3H mouse mammary carcinoma and a variety of murine spontaneous tumors. Int J Radiat Oncol Biol Phys 42: 895–898
Hotter G, Closa D, Prats N, Pi F, Gelpi E and Rosello-Catafau, (1997) Free-radical enhancement promotes leukocyte recruitment through a PAF and LTB4 dependent mechanism. Free Rad Biol Med 22: 947–954
Iyer S, Chaplin DJ, Rosenthal DS, Boulares AH, Li L-Y and Smulson ME (1998) Induction of apoptosis in proliferating human endothelial cells by the tumor-specific anti-angiogenesis agent Combretastatin A-4. Cancer Res 58: 4510–4514
Kettle AJ and Winterbourn CC (1997) Myeloperoxidase: a key regulator of neutrophil oxidant production. Redox Report 3: 3–15
Kettle AJ, van Dalen CJ and Winterbourn CC (1997) Peroxynitrite and myeloperoxidase leave the same footprint in protein nitration. Redox Report 3: 257–258
Korbelik M, Cecic I and Shibuya H (1997) The role of nitric oxide in the response of cancerous lesions to photodynamic therapy. Recent Res Devel Photochem Photobiol 1: 267–276
Korbelik M, Parkins CS, Shibuya H, Cecic I, Stratford MRL and Chaplin DJ (2000) Nitric oxide production by tumour tissue: impact on the response to photodynamic therapy. Br J Cancer 82: 1835–1843
Kubes P, Suzuki M and Granger DN (1991) Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 88: 4651
Parkins CS, Hill SA, Longergan SJ, Horsman MR, Chadwick JA and Chaplin DJ (1994) Ischaemia induced cell death in tumours: importance of temperature and pH. Int J Radiat Oncol Biol Phys 29: 499–503
Parkins CS, Dennis MF, Stratford MRL, Hill SA and Chaplin DJ (1995) Ischaemia-reperfusion injury in solid tumors: the role of oxygen radicals and nitric oxide. Cancer Res 55: 6026–6029
Parkins CS, Hill SA, Stratford MRL, Dennis MF and Chaplin DJ (1997) Metabolic and clonogenic consequences of ischaemia-reperfusion insult in solid tumours. Exp Physiol 82: 361–368
Parkins CS, Holder AL, Dennis MF, Stratford MRL and Chaplin DJ (1998) Involvement of oxygen free radicals in ischaemia-reperfusion injury in murine tumours: role of nitric oxide. Free Rad Res 28: 271–281
Pettit GR, Singh SB, Hamel E, Lin CM, Alberts DS and Garcia-Kendall D (1989) Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4. Experientia 45: 209–211
Skoufias D and Wilson L (1998) Assembly and colchicine binding characteristics of tubulin with maximally tyrosinated and detyrosinated α-tubulins. Arch Biochem Biophys 351: 115–122
Tozer GM, Prise VE, Wilson JI, Locke RJ, Vojnovic B, Stratford MRL, Dennis MF and Chaplin DJ (1999) Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues. Cancer Res 59: 1626–1634
Trotter MJ, Chaplin DJ and Olive PL (1989) Use of a carbocyanine dye as a marker of functional vasculature in murine tumours. Br J Cancer 59: 706–709
van der Vleit A, Eiserich JP, Halliwell B and Cross CE (1997) Formation of reactive nitrogen species during peroxidase-catalysed oxidation of nitrite. J Biol Chem 272: 7617–7625
Watts ME, Woodcock M, Arnold S and Chaplin DJ (1997) Effects of novel and conventional anti-cancer agents on human endothelial permeability: influence of tumour secreted factors. Anticancer Res 17: 71–76
Woods JA, Hadfield JA, Pettit GR, Fox BW and McGown AT (1995) The interaction with tubulin of a series of stilbenes based on combretastatin A-4. Br J Cancer 71: 705–711
Wink DA, Hanbauer I, Krishna MC, DeGraff W, Gamson J and Mitchell JB (1993) Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species. Proc Natl Acad Sci USA 90: 9813–9817
Zimmerman BJ, Landreneau FE and Granger DN (1992) The role of neutrophils in reperfusion injury. In. Molecular basis of oxidative damage by leucocytes. Jesaitis AJ, Drotz EA, (eds), pp 163–169. CRC Press: London
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Parkins, C., Holder, A., Hill, S. et al. Determinants of anti-vascular action by combretastatin A-4 phosphate: role of nitric oxide. Br J Cancer 83, 811–816 (2000). https://doi.org/10.1054/bjoc.2000.1361
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DOI: https://doi.org/10.1054/bjoc.2000.1361
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