BJR
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
British Journal of Radiology (2005) Supplement_27, 152-156
© 2005 British Institute of Radiology
doi: 10.1259/bjr/55705431
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cordes, N
Right arrow Articles by Meineke, V
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cordes, N
Right arrow Articles by Meineke, V
British Journal of Radiology Supplement_27 (2005),152-156 © 2005 The British Institute of Radiology

Full Paper

Modification of the cellular radiation survival and proliferation response by cell-matrix interactions: implications for integrin targeting in therapeutic approaches for radiation accident patients

N Cordes, MD and V Meineke, MD

Bundeswehr Institute of Radiobiology, Neuherbergstrasse 11, 80937 Munich, Germany

Correspondence: Dr Nils Cordes, MD, Bundeswehr Institute of Radiobiology, Neuherbergstrasse 11, 80937 Munich, Germany. E-mail: cordes@radiation-biology.de


   Abstract
Top
 Abstract
Introduction
 The impact of integrin-mediated...
 The putative therapeutic role...
 Conclusions and perspectives
 References
 
The pathophysiological mechanisms that lead to tissue destruction after exposure to ionising radiation are not fully understood. Recent observations showed that cell adhesion-mediating integrins and their signalling cascades affect cellular behaviour after genotoxic stress. Integrins play an important role in cell-matrix and cell-cell interactions and have been shown to be differentially expressed in irradiated tissue. As part of the immune response following irradiation, integrins may serve as critical membrane receptors on diverse normal cells such as leukocytes, platelets or fibroblasts. Modification of integrin function might influence multi-organ involvement and multi-organ failure, two life-threatening events that occur after irradiation. Both of these diseases are predominantly triggered by the immune system, and inhibition of integrin-mediated leukocyte stimulation could support the prevention of severe autoaggressive destruction of tissue. Here we review the evidence that cell-matrix interactions via focal adhesion-associated proteins and integrins, including their signal transduction pathways, play a crucial role in the cellular radiation response and the individual cell's fate after irradiation. In addition, the possible impact of clinically available anti-integrin treatment strategies for radiation accident patients is discussed.


   Introduction
Top
 Abstract
 Introduction
The impact of integrin-mediated...
 The putative therapeutic role...
 Conclusions and perspectives
 References
 
Radiation accidents are, fortunately, rare events, which occur mainly at, for example, nuclear power plant facilities and in atomic bomb scenarios [1, 2]. Nowadays one also has to consider the nuclear threat by terrorist attacks. In particular, this means that accidental radiation exposure may occur anywhere and that the number of injured, accidentally irradiated, people may be uncertain. Based on our restricted knowledge of the pathophysiological mechanisms following irradiation of normal tissue, the current therapeutic strategies consist mainly of the treatment of symptoms or, in more severe cases, bone marrow transplantation and intensive care [3]. New multitargeted therapeutic approaches are necessary to inhibit further destruction of vital organs or even to prevent the onset of acute radiation syndrome.

In recent years, the important role of radiation-damaged bone marrow, skin and gastrointestinal tract epithelium in the severity of the acute radiation illness has come to light [3, 4]. Irritation of these organ systems is critical in driving the destructive process from a circumscribed radiogenic lesion to a state of multi-organ involvement (MOI) or failure (MOF) [3]. Because tissue destruction is not only due to direct radiation-induced cell killing, other mechanisms such as activation of the immune system and subsequent autoaggressive digestion of parenchyma and tissues must be considered. These considerations could explain how the radiation-related destruction of tissue spreads and finally becomes manifested as MOI or MOF. Similar pathophysiological processes have been observed in non-radiation-related MOF [5]. A major determinant in these diseases is the immune system. Cell lysis/necrosis releases chemotactic molecules that recruit immunocompetent cells, which then serve as a driving force in the process of autoaggression. Not only interleukin receptors but also integrins are involved in the immune response and in the cellular responses of, for example, fibroblasts, epithelial cells and leukocytes following irradiation [6, 7].

Integrins are a family of 18{alpha} and 8{beta} homodimeric subunits that comprise at least 24 different transmembrane {alpha}{beta}-heterodimers depending on cell type and cellular context [8]. These cell adhesion receptors play a major role in interactions between cells and matrix proteins [8]. Lacking their own kinase ability, integrins signal via second messengers, GTPases, adapter proteins and in particular, {beta}1/{beta}2/{beta}3-integrin-bound integrin-linked kinase (ILK) and receptor-independent focal adhesion kinase (pp125FAK) [9, 10]. Downstream targets, e.g. src family members, AKT and MEK1/2, are subsequently involved in the regulation of survival, growth, gene transcription, differentiation, adhesion, migration, immune reactions, matrix protein production, secretion, etc. [11, 12].

Apart from the well known effects of cytokines and growth factors on the cellular radiation response [13, 14], studies of the effects of matrix proteins add a new facet to the complex behaviour of a single cell or a tissue following irradiation [15–18]. In fact, "network thinking" has just started and provides a far more realistic model of how all the diverse growth factor and adhesion receptor signalling cascades are connected [19]. For example, distinct areas in the cell membrane, called focal adhesions, in which integrins and growth factor receptors co-localise, enable intimate exchange of information for inside-out as well as outside-in signalling [20, 21]. This means that signals from the extracellular space modulate events inside the cells and vice versa.

Because the whole array of abovementioned cell functions are influenced by ionising radiation and has been in part in the spotlight among physicians and scientists, detailed examination of cell-matrix interactions and their impact on the cellular radioresponse, as well as radiation-dependent modulation of the extracellular matrix (ECM), motility and cell-cell contact are an important, innovative and growing field of interest [15, 22, 23].

This brief report will aim to give a short introduction into the field. As elucidated during the Reisensburg Conference on multiple organ failure and involvement following ionising radiation, damage to the bone marrow and skin organ systems appear to be life-limiting. Both of these systems have been investigated in detail in the past with regard to cell-matrix interactions and the role of integrins [24, 25]. Highly interesting data generated in clinical trials employing anti-integrins or peptidomimetics for inhibition of integrin function on leukocytes and thrombocytes showed that these new approaches reduce inflammatory responses and autoimmune progression in inflammatory bowel disease, multiple sclerosis, asthma therapy or re-stenosis after myocardial infarction [26]. Thus, it is hypothesised here that similar treatment regimens are likely to lead to a benefit in the therapy and outcome of radiation accident patients.


   The impact of integrin-mediated cell-matrix interactions on the radiation survival and proliferation response
Top
 Abstract
 Introduction
 The impact of integrin-mediated...
The putative therapeutic role...
 Conclusions and perspectives
 References
 
The observation that adhesion of normal and transformed cells to ECM proteins reduces cellular radiation sensitivity appears to be a widespread phenomenon [16, 27, 28]. Despite the differential impact of diverse matrix proteins on integrin cell surface presentation, cell cycle distribution, expression and activity patterns of protein kinases, the radiation survival outcome is improved in the presence of a variety of ECM proteins compared with culture plastic [29]. Identification of integrin downstream cytoplasmic signalling molecules such as ILK, FAK, paxillin and p130Cas in the cellular radiation response has already provided important insights [29–31]. Referring to our own studies, ILK is certainly an important molecular effector within the cellular radioresponse [18]. Activated by integrin-ligand binding, this protein kinase transduces signals downstream to critical survival and proliferation regulators such as AKT and GSK-3{beta}. Most interestingly, ILK overexpression demonstrated increased radiation sensitivity in contrast to radiation sensitivity-reducing FAK [30].

In addition to cell-matrix interactions, cell-cell contact showed modification of radiation survival and proliferation responses [32]. Cells grown in spheroids are more resistant to ionising radiation than their two-dimensionally-growing counterparts [33] or cells mutated in gap junction-forming connexins [34]. Examinations on confluently growing A549 cultures on fibronectin suggest that, although confluency reduced the radiosensitivity, adhesion to fibronectin had a far greater effect on the reduction of cellular radiosensitivity [32]. Further studies addressing the issue of cell-cell and cell-matrix interactions in more depth need to be performed.

However, examination of cell adhesion-mediated survival after genotoxic stress has provided controversial data during the past few years. Studies in a variety of transformed cell lines showed that adhesion is essential for certain cell functions to be executed [35]. For example, irradiation of HT1080 fibrosarcoma cells only induced apoptosis in cases of cell adhesion. Despite identifying p53, Arf, c-Abl and ILK as possible candidates within this mechanism [35], the cellular context, the molecular players and the exact signalling modes still remain elusive.

Overall, mimicking the in vivo microenvironment is a Sisyphus-like approach, because many interactions and molecules are absent or altered in cells on single or multicomponent matrix protein mixtures, in spheroids or in three-dimensional (3D) cultures. Nevertheless, recent studies of ECM-dependent modification of drug and radiation sensitivities rigorously question the impact and evaluation of in vitro cytotoxicity assays with regard to data interpretation and consequences for therapeutic anticancer strategies [25, 33, 36]. Differences in integrin localization and content, arrangement of actin and actin-associated proteins such as paxillin, as well as certain integrin signal-mediating protein kinases such as ILK and FAK can be detected in 3D matrix focal adhesions compared with 2D matrix focal adhesions [37, 38]. Enhanced cell biological activities and narrowed integrin usage were also observed in vivo [20, 37]. These distinctive in vivo 3D matrix focal adhesions might be more biologically relevant to living organisms than their 2D counterparts. Standardized and optimized experimental models would strongly improve the evaluation and interpretation of data generated in vitro with respect to the reactions of different irradiated normal and malign tissues. It is therefore highly recommended that future studies on radiation-induced pathophysiological processes should consider more intensively the complexity of tissue architecture and multiple receptor network signalling for regulation of survival and proliferation.


   The putative therapeutic role of integrin-targeted treatments for radiation accident patients
Top
 Abstract
 Introduction
 The impact of integrin-mediated...
 The putative therapeutic role...
Conclusions and perspectives
 References
 
Being aware of the fact that radiation sensitivity is not strictly an autonomous cell characteristic but is also triggered by the cell's microenvironment, the identification of the underlying molecular interactions between integrin-growth factor receptor-related signalling and their exact regulatory functions would certainly help to optimise and promote innovative normal tissue protection strategies as well as to uncover valuable biological indicators and/or target molecules for the assessment of radiation exposure in vivo.

Cell adhesion molecules (CAMs) of both the integrin and immunoglobulin families have been in the spotlight for many years [8]. Their involvement in leukocyte activation, leukocyte-endothelium interactions and chemotaxis during inflammatory responses, and platelet function in aggregation, bleeding and thrombosis were among the first observations and identified the essential role of CAMs for specific cell functions [7]. In particular, haematopoiesis, which is already altered after low doses of ionising radiation such as 0.2 Gy, depends on the complex and specific interactions of stem cells and progenitors with ECM ligands present in the marrow but not in other microenvironments [24, 39]. Differentiation of progenitors is guided by adhesion to ECM components or cytokine-presenting stromal cells [40]. These events are likely to serve as proliferation or survival signals, or cell adhesion itself may modify cytokine- or growth-factor-dependent signals. On the one hand understanding these processes could enable development of bone marrow stimulating substances that substitute for or synergistically act in combination with, for example, granulocyte colony-stimulating factor (G-CSF) [4]. On the other hand, the haematopoietic process might be modified by the use of newly designed agents following irradiation in terms of radioprotection.

The severe effects seen after high doses of ionising radiation appear to be based on two mechanisms: (a) ionising radiation destroys the irradiated cells directly; and (b) dying cells release immunostimulating factors and recruit remaining functional leukocytes, which participate in the elimination of damaged cells (two-hit model) [5]. Alterations of platelets and organ-specific parenchyma function, disseminated intravascular coagulation, adult respiratory distress syndrome (ARDS), renal failure, etc., are further characteristics of MOF [41]. Because anti-inflammatory therapies only indicate appropriate inhibition of these severe cellular responses following irradiation to a certain degree [2, 3], new approaches that target other molecules involved in this cascade of activation and self-destruction could prove useful and may lead to an additive or even supra-additive inhibitory effect. Targeting integrins on leukocytes might abrogate autoaggressiveness; targeting of platelets could preserve integrity of the vasculature and blood flow [26].

During the last decade, therapeutic anti-integrin approaches have implicated engineered antibodies or peptidomimetics with clinical success [42, 43]. For example, some {alpha}IIb{beta}3-integrin antagonists have already entered the clinic for prevention of cardiovascular complications or the treatment of cancer [43, 44]. Most of the compounds tested with a high degree of specificity were anti-{alpha}v{beta}3 or anti-RGD (Arg-Gly-Asp) peptides for blocking the RGD receptor subset of integrins (reviewed in [26]). {alpha}v{beta}3-integrins predominantly serve in angiogenic events [44], others such as {alpha}5{beta}1 are involved in survival signalling [45] or inhibit migration as observed for anti-RGD peptides [42]. With regard to antiangiogenesis and wound healing, neither systemic increase in bleeding nor impairment of would healing repair appeared [44]. Thus, it is likely that detrimental effects are also absent in the treatment of radiation accident patients using anti-integrin receptor targeting on leukocytes for anti-inflammation. Potential compounds currently available and in clinical trials are given in Table 1Go.


View this table:
[in this window]
[in a new window]
  		Table 1. Summary of potential integrin antagonists

 
Questions to be answered in the future concern the differentiation of pro- and anti-survival effects of specific CAMs, i.e. integrins and immunoglobulin family, within the radiation response of tissues. How important are the converging pathways between integrins and growth factor receptors and can they be modulated to protect normal tissues? Is it beneficial for organ survival and prevention of MOF to combine anti-integrin and anti-inflammatory therapies with each other and maybe inhibitors for matrix metalloproteinases [46] either to completely stop self-destruction of organs or to rescue parts of the parenchyma to provide functionality?

In addition to these provocative, innovative concepts, studies on radioprotective substances for normal tissues have been intensively performed in the past with limited success [47–49]. Administration of the well known substance WR-2721 (2-[(3-aminopropyl)amino]ethane-thiol dihydrogen phosphate ester), called Amifostine, or growth factors such as keratinocyte growth factor (KGF) demonstrated radioprotective effects of normal tissue in therapeutically irradiated patients with, for example, head and neck or colorectal cancer [47]. In contrast to KGF, reports on the efficacy of Amifostine are controversial [48] and will not be discussed further here. However, the prevention of severe oral mucositis indicates advances in the therapeutic strategies to protect normal tissues against ionising radiation. New substances and combinations of various agents, as in part suggested herein, must be tested in future trials to identify potent treatment schedules.


   Conclusions and perspectives
Top
 Abstract
 Introduction
 The impact of integrin-mediated...
 The putative therapeutic role...
 Conclusions and perspectives
References
 
Cell-matrix interactions influence the cellular radioresponse. In vitro and in vivo data similarly underscore this fact and future studies will help to uncover the underlying molecular mechanisms. First, clinical trials could be based on new insights for optimisation of treatment schedules in accidentally irradiated persons to prevent MOF or MOI. In vitro evaluation of the therapeutic impact of combined integrin, growth factor receptor and matrix metalloproteinase inhibitors should be the first step on the way to clinical trials, which will be difficult to accomplish owing to, fortunately, a very small number of radiation accidents.


   Acknowledgments
 
The authors would like to thank Dr Gordon C Tucker for providing detailed and essential information of potential anti-integrin compounds.


   References
Top
 Abstract
 Introduction
 The impact of integrin-mediated...
 The putative therapeutic role...
 Conclusions and perspectives
 References
 

  1. Moulder JE. Post-irradiation approaches to treatment of radiation injuries in the context of radiological terrorism and radiation accidents: a review. Int J Radiat Biol 2004;80:3–10.[Medline]
  2. Meineke V, van Beuningen D, Sohns T, Fliedner TM. Medical management principles for radiation accidents. Mil Med 2003;168:219–22.[Medline]
  3. Turai I, Veress K, Gunalp B, Souchkevitch G. Medical response to radiation incidents and radionuclear threats. BMJ 2004;328:568–72.[Free Full Text]
  4. Dainiak N, Waselenko JK, Armitage JO, MacVittie TJ, Farese AM. The hematologist and radiation casualties. Hematology (Am Soc Hematol Educ Program)2003:473–96.
  5. Rotstein OD. Modeling the two-hit hypothesis for evaluating strategies to prevent organ injury after shock/resuscitation. J Trauma 2003;54(5 Suppl.):S203–6.
  6. Piela-Smith TH, Aune T, Aneiro L, Nuveen E, Korn JH. Impairment of lymphocyte adhesion to cultured fibroblasts and endothelial cells by gamma-irradiation. J Immunol 1992;148:41–6.[Abstract]
  7. Stoolman LM. Adhesion molecules controlling lymphocyte migration. Cell 1989;56:907–10.[Medline]
  8. Hynes RO. Integrins: bi-directional, allosteric signaling machines. Cell 2002;110:673–87.[Medline]
  9. Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J, et al. Regulation of cell adhesion and anchorage-dependent growth by a new {beta}1-integrin-linked protein kinase. Nature 1996;379:91–6.[Medline]
  10. Schaller MD. Biochemical signals and biological responses elicited by the focal adhesion kinase. Biochim Biophys Acta 2001;1540:1–21.[Medline]
  11. Assoian RK. Anchorage-dependent cell cycle progression. J Cell Biol 1997;136:1–4.[Free Full Text]
  12. Watt FM. Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J 2002;21:19–26.
  13. Neta R, Oppenheim JJ, Douches SD. Interdependence of the radioprotective effects of human recombinant interleukin 1{alpha}, tumor necrosis factor {alpha}, granulocyte colony-stimulating factor, and murine recombinant granulocyte-macrophage colony-stimulating factor. J Immunol 1988;140:108–11.[Abstract]
  14. Ruifrok AC, McBride WH. Growth factors: biological and clinical aspects. Int J Radiat Oncol Biol Phys 1999;43:877–81.[Medline]
  15. Giannopoulou E, Katsoris P, Hatziapostolou M, Kardamakis D, Kotsaki E, Polytarchou C, et al. X-rays modulate extracellular matrix in vivo. Int J Cancer 2001;94:690–8.[Medline]
  16. Cordes N, Meineke V. Cell adhesion-mediated radioresistance (CAM-RR): extracellular matrix-dependent improvement of cell survival in human tumor and normal cells in vitro. Strahlenther Onkol 2003;179:337–44.[Medline]
  17. Cordes N, Meineke V. Integrin signaling and the cellular response to ionizing radiation. J Mol Histol 2004;35:327–37.[Medline]
  18. Cordes N. Overexpression of hyperactive integrin-linked kinase leads to increased cellular radiosensitivity. Cancer Res 2004;64:5683–92.[Abstract/Free Full Text]
  19. Moro L, Dolce L, Cabodi S, Bergatto E, Erba EB, Smeriglio M, et al. Integrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosines. J Biol Chem 2002;277:9405–14.[Abstract/Free Full Text]
  20. Yamada KM, Even-Ram S. Integrin regulation of growth factor receptors. Nat Cell Biol 2002;4:E75–6.[Medline]
  21. Burridge K, Fath K, Kelly T, Nuckolls G, Turner C. Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. Annu Rev Cell Biol 1988;4:487–525.[Medline]
  22. Jacobsen K, Kravitz J, Kincade PW, Osmond DG. Adhesion receptors on bone marrow stromal cells: in vivo expression of vascular cell adhesion molecule-1 by reticular cells and sinusoidal endothelium in normal and gamma-irradiated mice. Blood 1996;87:73–82.[Abstract/Free Full Text]
  23. Krotz F, Schiele TM, Zahler S, Konig A, Rieber J, Kantlehner R, et al. Sustained platelet activation following intracoronary beta irradiation. Am J Cardiol 2002;90:1381–4.[Medline]
  24. Simmons PJ, Zannettino A, Gronthos S, Leavesley D. Potential adhesion mechanisms for localization of haemopoietic progenitors to bone marrow stroma. Leuk Lymphoma 1994;12:353–63.[Medline]
  25. Meineke V, Müller K, Ridi R, Cordes N, Köhn FM, Mayerhofer A, et al. Development and evaluation of a skin organ model for the analysis of radiation effects. Strahlenther Onkol 2004;180:102–8.[Medline]
  26. Tucker GC. Inhibitors of integrins. Curr Opin Pharmacol 2002;2:394–402.[Medline]
  27. Rose RW, O'Hara MO, Williamson SK, Grant DS. The role of laminin-1 in the modulation of radiation damage in endothelial cells and differentiation. Radiat Res 1999;152:14–28.[Medline]
  28. Fuks Z, Vlodavsky I, Andreeff M, McLoughlin M, Haimovitz-Friedman A. Effects of extracellular matrix on the response of endothelial cells to radiation in vitro. Eur J Cancer 1992;28:725–31.
  29. Cordes N, van Beuningen D. Cell adhesion to the extracellular matrix protein fibronectin modulates radiation-dependent G2 phase arrest involving integrin-linked kinase (ILK) and glycogen synthase kinase-3{beta} (GSK-3{beta}) in vitro. Br J Cancer 2003;88:1470–9.[Medline]
  30. Beinke C, van Beuningen D, Cordes N. Ionizing radiation modulates expression and tyrosine phosphorylation of the focal adhesion-associated proteins focal adhesion kinase (FAK) and its substrates p130cas and paxillin in A549 human lung carcinoma cells in vitro. Int J Radiat Biol 2003;79:721–31.[Medline]
  31. Kasahara T, Koguchi E, Funakoshi M, Aizu-Yokota E, Sonoda Y. Antiapoptotic action of focal adhesion kinase (FAK) against ionizing radiation. Antioxid Redox Signal 2002;4:491–9.[Medline]
  32. Cordes N, Beinke C. Fibronectin alters A549 human lung cancer cell survival after irradiation. Cancer Biol Ther 2004;3:47–53.[Medline]
  33. Frankel A, Buckman R, Kerbel RS. Abrogation of taxol-induced G2-M arrest and apoptosis in human ovarian cancer cells grown as multicellular tumor spheroids. Cancer Res 1997;57:2388–93.[Abstract/Free Full Text]
  34. Luo C, MacPhail SH, Dougherty GJ, Naus CC, Olive PL. Radiation response of connexin43-transfected cells in relation to the "contact effect". Exp Cell Res 1997;234:225–32.[Medline]
  35. Lewis JM, Truong TN, Schwartz MA. Integrins regulate the apoptotic response to DNA damage through modulation of p53. Proc Natl Acad Sci USA 2002;99:3627–32.[Abstract/Free Full Text]
  36. Cordes N, Beinke C, Plasswilm L, van Beuningen D. Irradiation and various cytotoxic drugs enhance tyrosine phosphorylation and {beta}1-integrin clustering in human A549 lung cancer cells in a substratum-dependent manner in vitro. Strahlenther Onkol 2004;180:157–64.[Medline]
  37. Cukierman E, Pankov R, Stevens DR, Yamada KM. Taking cell-matrix adhesions to the third dimension. Science 2001;294:1708–12.[Abstract/Free Full Text]
  38. Gruber HE, Hanley EN Jr. Human disc cells in monolayer vs 3D culture: cell shape, division and matrix formation. BMC Musculoskelet Disord 2000;1:1.[Medline]
  39. Papayannopoulou T, Craddock C. Homing and trafficking of hemopoietic progenitor cells. Acta Haematol 1997;97:97–104.[Medline]
  40. Fliedner TM. Prologue to characteristics and potentials of blood stem cells. Stem Cells 1998;16(Suppl. 1):357–60.
  41. Baue AE, Durham R, Faist E. Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle? Shock 1998;10:79–89.[Medline]
  42. Mousa SA. Anti-integrin as novel drug-discovery targets: potential therapeutic and diagnostic implications. Curr Opin Chem Biol 2002;6:534–41.[Medline]
  43. Leclerc JR. Platelet glycoprotein IIb/IIIa antagonists: lessons learned from clinical trials and future directions. Crit Care Med 2002;30(Suppl.):S332–40.
  44. Gutheil JC, Campbell TN, Pierce PR, Watkins JD, Huse WD, Bodkin DJ, et al. Targeted anti-angiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin {alpha}v{beta}3. Clin Cancer Res 2000;6:3056–61.[Abstract/Free Full Text]
  45. Trikha M, Zhou Z, Timar J, Raso E, Kennel M, Emmell E, et al. Multiple roles for platelet GPIIb/IIIa and {alpha}v{beta}3 integrins in tumor growth, angiogenesis, and metastasis. Cancer Res 2002;62:2824–33.[Abstract/Free Full Text]
  46. Liotta LA, Stetler-Stevenson WG. Metalloproteinases and cancer invasion. Semin Cancer Biol 1999;1:99–106.
  47. Dörr W, Spekl K, Farrell CL. The effect of keratinocyte growth factor on healing of manifest radiation ulcers in mouse tongue epithelium. Cell Prolif 2002;35(Suppl. 1):86–92.
  48. Openshaw H, Beamon K, Synold TW, Longmate J, Slatkin NE, Doroshow JH, et al. Neurophysiological study of peripheral neuropathy after high-dose Paclitaxel: lack of neuroprotective effect of amifostine. Clin Cancer Res 2004;10:461–7.[Abstract/Free Full Text]
  49. Yu Z, Eaton JW, Persson HL. The radioprotective agent, amifostine, suppresses the reactivity of intralysosomal iron. Redox Rep 2003;8:347–55.[Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cordes, N
Right arrow Articles by Meineke, V
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cordes, N
Right arrow Articles by Meineke, V

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
BJR DMFR IMAGING  ALL BIR JOURNALS