Thomlinson RH, Gray LH, The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 1955, 9, 539-579. [PubMed]
Boag JW, Oxygen diffusion and oxygen depletion problems in radiobiology. In: Current Topics in Radiation Research V. Amsterdam: North Holland, 1969, pp141-1195.
Brown JM, Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. Brit J Radiol 1979, 52, 650-656.
Trotter MJ, Chaplin DJ, Durand RE, Olive PL, The use of fluorescent probes to identify regions of transient perfusion in murine tumors. Int J Radiat Oncol Biol Phys 1989, 16, 931-934.
Chaplin DJ, Peters CE, Horsman MR, Trotter MJ, Drug induced perturbations in tumour blood flow: therapeutic potential and possible limitations. Radioth Oncol 1991, 20, Suppl.1, 93-101.
Dewhirst MW, Kimura H, Rehmus SW, Braun RD, Papahadjopoulos D, Hong K, Secomb TW, Microvascular studies on the origins of perfusion-limited hypoxia. Brit J Cancer 1996, 27, S247-S251.
Dewhirst MW, Ong ET, Braun RD, Smith B, Klitzman B, Evans SM, Wilson D, Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia. Brit J Cancer 1999, 79, 1717-1722.
Cardenas-Navia LI, Mace D, Richardson RA, Wilson DF, Shan S, Dewhirst MW, The Pervasive Presence of Fluctuating Oxygenation in Tumors. Cancer Res 2008, 68, 5812-5819. [Web of Science]
Yasui H, Matsumoto S, Devasahayam N, Munasinghe JP, Choudhuri R, Saito K, Subramanian S, Mitchell JB, Krishna MC, Low field magnetic resonance imaging to visualize chronic and cycling hypoxia in tumor-bearing mice. Cancer Res 2010, 15, 6427-6436.
Arbeit JM, Brown JM, Chao KSC, Chapman JD, Eckelman WC, Fyles AW, Giaccia AJ, Hill RP, Koch CJ, Krishna MC, Krohn KA, Lewis JS, Mason RP, Melillo G, Padhani AR, Powis G, Rajendran JG, Reba R, Robinson SP, Semenza GL, Swartz HM, Vaupel P, Yang D, Hypoxia: Importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol 2006, 82, 699-757.
Rofstad EK, Gaustad JV, Egeland TAM, Mathiesen B, Galappanthi K, Tumors exposed to acute cycling hypoxic stress show enhanced angiogenesis, perfusion and metastatic dissemination. Int J Cancer 2010, 127, 1535-1546. [Web of Science]
Bayer C, Shi K, Astner ST, Maftei C-A, Vaupel P, Acute versus chronic hypoxia: why a simplified classification is simply not enough. Int J radiat Oncol Biol Phys 2011, 80, 965-968. [PubMed] [Web of Science]
Koch CJ, Measurement of Absolute Oxygen Levels in Cells and Tissues using Oxygen Sensors and the 2-nitroimidazole EF5. In: Methods in Enzymology – Antioxidants and Redox Cycling (Sen CK and Packer L, eds) San Diego: Academic Press, 2002, pp3-31.
Evans SM, Koch CJ, Joiner B, Jenkins WT, Laughlin KM, Lord EM, Identification of hypoxia in cells and tissues of epigastric 9L rat glioma using EF5 [2-(2-nitro-1H-imidazol-1- yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide]. Brit J Cancer 1995, 72, 875-882.
Evans SM, Jenkins WT, Joiner B, Lord EM, Koch CJ, 2-nitroimidazole (EF5) binding predicts radiation sensitivity in individual 9L subcutaneous tumors. Cancer Res 1996, 56, 405-411.
Koch CJ, Shuman AL, Jenkins WT, Kachur AV, Karp JS, Freifelder R, Dolbier WR, Evans SM, The radiation response of cells from 9L gliosarcoma tumors is correlated with [F18]- EF5 uptake. Int J Radiat Biol 2009, 85, 1137-1147.
Jenkins WT, Evans SM, Koch CJ, Hypoxia and necrosis in rat 9L glioma and Morris 7777 hepatoma tumors: comparative measurements using EF5 binding and Eppendorf needle electrode. Int J Rad Onc Biol Phys 2000, 46, 1005-1017.
Evans SM, Fraker DL, Hahn SM, Gleason K, Jenkins WT, Jenkins K, Hwang W-T, Zhang PD, Mick R, Koch CJ, EF5 binding and clinical outcome in human soft tissue sarcomas. Int J Radiat Oncol Biol Phys 2006, 64, 922-927. [PubMed]
Evans SM, Judy KD, Dunphy I, Jenkins WT, Nelson PT, Collins R, Wileyto EP, Jenkins K, Hahn SM, Stevens C, Judkins AR, Phillips P, Koch CJ, Comparative measurements of hypoxia in human brain tumors using needle electrodes and EF5 binding. Cancer Res 2004, 64, 1886-1892.
Evans SM, Jenkins KW, Jenkins WT, Dilling T, Judy KD, Schrlau A, Judkins A, Hahn SM, Koch CJ, Imaging and analytical methods for the evaluation of vasculature and hypoxia in human brain tumors. Radiat Res 2008, 170, 677- 690. [Web of Science]
Gullino PM, Grantham FH, Courtney AH, Losonczy I, Relationship between Oxygen and Glucose Consumption by Transplanted Tumors in Vivo. Cancer Res 1967, 27, 1041- 1052.
Zhou R, Pickup S, Yankeelov TE, Springer CS, Glickson JD, Simultaneous measurement of arterial input function and tumor pharmacokinetics in mice by dynamic contrast enhanced imaging: effects of transcytolemmal water exchange. Magnetic Reson Med 2004, 52, 248-257.
Landis CS, Li X, Telang FWea, Determination of the MRI contrast agent concentration time course in vivo following bolus injection: effect of equilibrium transcytolemmal water exchange. Magn Reson Med 2000, 44, 563-574. [PubMed]
Kim S, Quon H, Loevner LA, Rosen MA, Dougherty L, Kilger AM, Glickson JD, Poptani H, Transcytolemmal water exchange in pharmacokinetic analysis of dynamic contrastenhanced MRI data in squamous cell carcinoma of the head and neck. J Magn Reson Imaging 2007, 26, 1607-1617. [Web of Science]
Wong J, Armour E, Kazanzides P, Iordachita I, Tryggestad E, Deng H, Matinfar M, Kennedy C, Liu Z, Chan Y, Gray O, Verhaegen F, McNutt T, Ford E, DeWeese TL, Highresolution, small animal radiation research platform with x-ray tomography guidance capability. Int J Radiat Oncol Biol Phys 2008, 71, 1591-1599.
Clyman RI, Chan CY, Mauray F, Chen YQ, Cox W, Seidner SR, Weiss H, Lord EM, Waleh N, Evans SM, Koch CJ, Permanent anatomic closure of the newborn ductus arteriosus: the roles of postnatal constriction, hypoxia and gestation. Pediatric Res 1999, 45, 19-29. [CrossRef]
Olive PL, Banath JP, Phosphorylation of histone H2AX as a measure of radiosensitivity. Int J Radiat Oncol Biol Phys 2004, 58, 331-335.
Evans SM, Schrlau A, Chalian AA, Zhang P, Koch CJ, Oxygen levels in normal and previously irradiated human skin as assessed by EF5 binding. J Invest Dermatol 2006, 126, 2596-2606.
Trotter MJ, Olive PL, Chaplin DJ, Effect of vascular marker Hoechst 33342 on tumour perfusion and cardiovascular function in the mouse. Brit J Cancer 1990, 62, 903-908. [CrossRef]
Chaplin DJ, Durand RE, Olive PL, Acute hypoxia in tumors: Implications for modifiers of radiation effects. Int J Radiat Biol Phys 1986, 12, 1279-1282.
Janssens GO, Rademakers SE, Terhaard CH, Doornaert PA, Bijl HP, van den Ende P, Chin A, Marres HA, de Bree R, van der Kogel AJ, Hoogsteen IJ, Bussink J, Span PN, Kaanders JH, Accelerated Radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomixed trial. J Clin Oncol 2012, 30, 1777-1783. [PubMed] [Web of Science]
Komar G, Seppänen M, Eskola O, Lindholm P, Grönroos JT, Forsback S, Sipilä H, Evans SM, Solin O, Minn H, 18F-EF5: A new PET tracer for imaging hypoxia in head and neck cancer. J Nuc Med 2008, 49, 1-8.
Devic S, Tomic N, Faria S, Menard S, Lisbona R, Lehnert, S, Defining Radiotherapy Target volumes based on FDG-PET/ CT scan: still a Pandora’s box. Int J radiat Oncol Biol Phys 2010, 78, 1555-1562. [Web of Science]
Evans SM, Koch CJ, Re: Devic et. al.; Int J. radiat. Oncol. Biol. Phys, 79: 1555-1562, 2010. Int J Radiat Oncol Biol Phys 2011, 81, 902.
Horan AD, Giandomenico AR, Koch CJ, Effect of oxygen on radiation-induced DNA damage in isolated nuclei. Radiat Res 1999, 152, 144-153.
Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR, Dewhirst MW, Tissue oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. 1996, 941-943. [PubMed]
Fyles AW, Milosevic M, Wong R, Kavanagh MC, Pintilie M, Chapman W, Levin W, Manchul L, Keane TJ, Hill RP, Oxygenation predicts radiation response and survival in patients with cervix cancer. Radioth and Oncol 1998, 48, 149-156.
Milosevic M, Fyles A, Hedley D, Pintilie M, Levin W, Manchul L, Hill R, Interstitial fluid pressure predicts survival in patients with cervix cancer independent of clinical prognostic factors and tumor oxygen measurements. Cancer Res 2001, 61, 6400-6405.
Brat DJ, Van Meir EG, Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis and accelerated growth in glioblastoma. Laboratory Investigation 2004, 84, 397-405.
Koch CJ, Scheuermann JS, Divgi C, Judy KD, Kachur AV, Freifelder R, Reddin JS, Karp J, Stubbs JB, Hahn SM, Driesbaugh J, Smith D, Prendergast S, Evans SM, Biodistribution and dosimetry of 18F-EF5 in cancer patients with preliminary comparison of 18F-EF5 uptake versus EF5 binding in human glioblastoma. Eur J Nuc Med Mol Img 2010, 37, 2048-2059. [Web of Science]
Kim CS, Loevner LA, Hwang WT, Weinstein G, Chalian A, Quon H, Poptani H, Prediction of disease free survival in patients with squamous cell carcinomas of the head and neck using dynamic contrast enhanced MRI. Am J Neuroradiol 2011, 32, 778-784.
Toma-Dasu I, Waites A, Dasu A, Denekamp J, Theoretical simulation of oxygen tension measurement in tissues using a microelectrode: I The response function of the electrode. Physiological Measurement 2001, 22, 713-725.
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Mechanisms of blood flow and hypoxia production in rat 9L-epigastric tumors
1University of Pennsylvania, Department of Radiation Oncology, Perelman School of Medicine, Philadelphia, PA, 19104
2University of Pennsylvania, Department of Radiology, Perelman School of Medicine, Philadelphia, PA, 19104
©2012 Versita Sp. z o.o.. This content is open access.
Citation Information: Tumor Microenvironment and Therapy. Volume 1, Pages 1–13, ISSN (Online) 2299-1123, DOI: 10.2478/tumor-2012-0001, December 2012
- Published Online:
Classical descriptions of tumor physiology suggest two origins for tumor hypoxia; steady-state (diffusion-limited) hypoxia and cycling (perfusionmodulated) hypoxia. Both origins, primarily studied and characterized in murine models, predict relatively small, isolated foci or thin shells of hypoxic tissue interspersed with contrasting oxic tissue. These foci or shells would not be expected to scale with overall tumor size since the oxygen diffusion distance (determined by oxygen permeability and tissue oxygen consumption rate) is not known to vary dramatically from tumor to tumor. We have identified much larger (macroscopic) regions of hypoxia in rat gliosarcoma tumors and in larger human tumors (notably sarcomas and high-grade glial tumors), as indicated by biochemical binding of the hypoxia marker, EF5. Thus, we considered an alternative cause of tumor hypoxia related to a phenomenon first observed in window-chamber tumor models: namely longitudinal arteriole gradients. Although longitudinal arteriole gradients, as originally described, are also microscopic in nature, it is possible for them to scale with tumor size if tumor blood flow is organized in an appropriate manner. In this organization, inflowing blood would arise from relatively well-oxygenated sources and would branch and then coalesce to poorly-oxygenated outflowing blood over distances much larger than the length of conventional arterioles (multi-millimeter scale). This novel concept differs from the common characterization of tumor blood flow as disorganized and/or chaotic. The organization of blood flow to produce extended longitudinal gradients and macroscopic regional hypoxia has many important implications for the imaging, therapy and biological properties of tumors. Herein, we report the first experimental evidence for such blood flow, using rat 9L gliosarcoma tumors grown on the epigastric artery/vein pair.