Tumor hypoxia at the micro-regional level: Clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers

Radiotherapy and Oncology

Volumn 67, Issue 1, 2003, Pages 3-15

  Bussink, Johan ^a   Kaanders, Johannes H A M ^a   Van Der Kogel, Albert J ^a  

^a RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

CA9; Eppendorf; Glut; HIF; Hypoxia; Pimonidazole; Proliferation; Tumor

Indexed keywords

2 (2 NITRO 1H IMIDAZOL 1 YL) N (2,2,3,3,3 PENTAFLUOROPROPYL)ACETAMIDE; 2 NITROIMIDAZOLE; CARBONATE DEHYDRATASE; CARBONATE DEHYDRATASE IX; CELL MARKER; GLUCOSE TRANSPORTER 1; GLUCOSE TRANSPORTER 3; HOE 33342; HYPOXIA INDUCIBLE FACTOR 1ALPHA; NITROIMIDAZOLE; OXYGEN; PIMONIDAZOLE; UNCLASSIFIED DRUG; VASCULOTROPIN;

APOPTOSIS; CANCER RADIOTHERAPY; CANCER RESISTANCE; CARDIOVASCULAR SYSTEM; CELL HYPOXIA; CELL PROLIFERATION; CLONOGENESIS; GENE; HUMAN; HYPOXEMIA; IMMUNOHISTOCHEMISTRY; MICROELECTRODE; MICROENVIRONMENT; OXYGEN BLOOD LEVEL; OXYGEN CONSUMPTION; OXYGEN ELECTRODE; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SOLID TUMOR; TISSUE OXYGENATION; TISSUE PERFUSION; TUMOR DIFFERENTIATION; TUMOR GROWTH; TUMOR VASCULARIZATION;

EID: 0038523737     PISSN: 01678140     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0167-8140(03)00011-2     Document Type: Review

References (161)

1. Aebersold D.M., Beer K.T., Laissue J., et al. Intratumoral microvessel density predicts local treatment failure of radically irradiated squamous cell cancer of the oropharynx. Int J Radiat Oncol Biol Phys. 48:2000;17-25.
2. Aebersold D.M., Burri P., Beer K.T., et al. Expression of hypoxia-inducible factor-1 a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res. 61:2001;2911-2916.
3. Airley R., Loncaster J., Davidson S., et al. Glucose transporter Glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix. Clin Cancer Res. 7:2001;928-934.
4. Arteel G.E., Thurman R.G., Yates J.M., Raleigh J.A. Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br J Cancer. 72:1995;889-895.
5. Beasley N.J.P., Wykoff C.C., Watson P.H., et al. Carbonic anhydrase IX, an endogenous hypoxia marker, expression in head and neck squamous cell carcinoma and its relationship to hypoxia, necrosis, and microvessel density. Cancer Res. 61:2001;5262-5267.
6. Begg A.C., Haustermans K., Hart A.A.M., et al. The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis. Radiother Oncol. 50:1999;13-23.
7. Bennett M.H., Wilson G.D., Dische S., et al. Tumour proliferation assessed by combined histological and flow cytometric analysis: implications for therapy in squamous cell carcinoma in the head and neck. Br J Cancer. 65:1992;870-878.
8. Bernsen H.J., Rijken P.F., Oostendorp T., van der Kogel A.J. Vascularity and perfusion of human gliomas xenografted in the athymic nude mouse. Br J Cancer. 71:1995;721-726.
9. Birner P., Schindl M., Obermair A., Plank C., Breitenecker G., Oberhuber G. Overexpression of hypoxia-inducible factor 1a is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res. 60:2000;4693-4696.
10. Birner P., Gatterbauer B., Oberhuber G., et al. Expression of hypoxia-inducible factor-1 alpha in oligodendrogliomas: its impact on prognosis and on neoangiogenesis. Cancer. 92:2001;165-171.
11. Björk-Eriksson T., West C.M.L., Cvetskovska E., et al. The lack of correlation between proliferation (Ki-67. PCNA, LI, Tpot), p53 expression and radiosensitivity for head and neck cancers. Br J Cancer. 80:1999;1400-1404.
12. Bonner J.A., Raisch K.P., Trummell H.Q., et al. Enhanced apoptosis with combination C225/radiation treatment serves as the impetus for clinical investigation in head and neck cancers. J Clin Oncol. 18:2000;47S-53S.
13. Brewer C.A., Liao S.Y., Wilczynski S.P., et al. A study of biomarkers in cervical carcinoma and clinical correlation of the novel biomarker MN. Gynecol Oncol. 63:1996;337-344.
14. Brizel D.M., Scully S.P., Harrelson J.M., et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 56:1996;941-943.
15. Brizel D.M., Sibley G.S., Prosnitz L.R., Scher R.L., Dewhirst M.W. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 38:1997;285-289.
16. Brizel D.M., Dodge R.K., Clough R.W., Dewhirst M.W. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol. 53:1999;113-117.
17. Brown J.M. Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. Br J Radiol. 52:1979;650-656.
18. Brown J.M., Siim B.G. Hypoxia-specific cytotoxins in cancer therapy. Semin Radiat Oncol. 6:1996;22-36.
19. Brown J.M. Therapeutic targets in radiotherapy. Int J Radiat Oncol Biol Phys. 49:2001;319-326.
20. Brown R.S., Wahl R.L. Overexpression of Glut-1 glucose transporter in human breast cancer. An immunohistochemical study. Cancer. 72:1993;2979-2985.
21. Bussink J., Kaanders J.H.A.M., Rijken P.F.J.W., et al. Vascular architecture and microenvironmental parameters in human squamous cell carcinoma xenografts: effects of carbogen and nicotinamide. Radiother Oncol. 50:1999;173-184.
22. Bussink J., Kaanders J.H.A.M., Rijken P.F.J.W., Raleigh J.A., van der Kogel A.J. Changes in blood perfusion and hypoxia after irradiation of a human squamous cell carcinoma xenograft tumor line. Radiat Res. 153:2000;398-404.
23. Bussink J., Kaanders J.H.A.M., Strik A.M., van der Kogel A.J. Effects of nicotinamide and carbogen on oxygenation in human tumor xenografts measured with luminescense-based fiber optic probes. Radiother Oncol. 57:2000;21-30.
24. Bussink J., Kaanders J.H.A.M., Strik A.M., Vojnovic B., van der Kogel A.J. Optical sensor-based oxygen tension measurements correspond with hypoxia marker binding in three human tumor xenograft lines. Radiat Res. 154:2000;547-555.
25. Cantuaria G., Fagotti A., Ferrandina G., et al. Glut-1 expression in ovarian carcinoma: association with survival and response to chemotherapy. Cancer. 92:2001;1144-1150.
26. Carmeliet P., Dor Y., Herbert J.M., et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 394:1998;485-490.
27. Chia S.K., Wykoff C.C., Watson P.H., et al. Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol. 19:2001;3660-3668.
28. Cline J.M., Thrall D.E., Rosner G.L., Raleigh J.A. Distribution of the hypoxia marker CCI-103F in canine tumors. Int J Radiat Oncol Biol Phys. 28:1994;921-933.
29. Collingridge D.R., Young W.K., Vojnovic B., et al. Measurement of tumor oxygenation: a comparison between polarographic needle electrodes and a time-resolved luminescence-based optical sensor. Radiat Res. 147:1997;329-334.
30. Craighead P.S., Pearcey R., Stuart G. A phase I/II evaluation of tirapazamine administered intravenously concurrent with cisplatin and radiotherapy in women with locally advanced cervical cancer. Int J Radiat Oncol Biol Phys. 48:2000;791-795.
31. Dasu A., Denekamp J. New insights into factors influencing the clinically relevant oxygen enhancement ratio. Radiother Oncol. 46:1998;269-277.
32. Denhart B.C., Guidi A.J., Tognazzi K., Dvorak H.F., Brown L.F. Vascular permeability factor/vascular endothelial growth factor and its receptors in oral and laryngeal squamous cell carcinoma and dysplasia. Lab Invest. 77:1997;659-664.
33. Dewhirst M.W. Concepts of oxygen transport at the microcirculatory level. Semin Radiat Oncol. 8:1998;143-150.
34. 2 gradients in window chamber tumours: impact on tumour hypoxia. Br J Cancer. 79:1999;1717-1722.
35. Durand R.E., Sham E. The lifetime of hypoxic human tumor cells. Int J Radiat Oncol Biol Phys. 42:1998;711-715.
36. Durand R.E., Raleigh J.A. Identification of nonproliferating but viable hypoxic cells in vivo. Cancer Res. 58:1998;3547-3550.
37. Evans S.M., Hahn S., Pook D.R., et al. Detection of hypoxia in human squamous cell carcinoma by EF5 binding. Cancer Res. 60:2000;2018-2024.
38. Fenton B.M. Effects of carbogen plus fractionated irradiation on KHT tumor oxygenation. Radiother Oncol. 44:1997;183-190.
39. 2 saturation measurements. Br J Cancer. 79:1999;464-471.
40. Foekens J.A., Schmitt M., van Putten W.L., et al. Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. J Clin Oncol. 12:1994;1648-1658.
41. Franko A.J., Sutherland R.M. Rate of death of hypoxic cells in multicell spheroids. Radiat Res. 76:1978;561-572.
42. Furudoi A., Tanaka S., Haruma K., et al. Clinical significance of human erythrocyte glucose transporter 1 expression at the deepest invasive site of advanced colorectal carcinoma. Oncology. 60:2001;162-169.
43. Fyles A., Milosevic M., Hedley D., et al. Tumor hypoxia has independent predictor impact only in patients with node-negative cervix cancer. J Clin Oncol. 20:2002;680-687.
44. Gatenby R.A., Kessler H.B., Rosenblum J.S., et al. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys. 14:1988;831-838.
45. Giatromanolaki A., Koukourakis M.I., Sivridis E., et al. Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small-cell lung cancer. Cancer Res. 61:2001;7992-7998.
46. Giatromanolaki A., Koukourakis M.I., Sivridis E., et al. Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer. 85:2001;881-890.
47. Gleadle J.M., Ratcliffe P.J. Hypoxia and the regulation of gene expression. Mol Med Today. 3:1998;122-129.
48. Gnarra J.R., Zhou S., Merrill M.J., et al. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci USA. 93:1996;10589-10594.
49. Goda F., O'Hara J.A., Rhodes E.S., et al. Changes of oxygen tension in experimental tumors after a single dose of X-ray irradiation. Cancer Res. 55:1995;2249-2252.
50. Graeber T.G., Osmanian C., Jacks T., et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 379:1996;88-91.
51. Haber R.S., Rathan A., Weiser K.R., et al. Glut-1 glucose transporter expression in colorectal carcinoma: a marker for poor prognosis. Cancer. 83:1998;34-40.
52. Hanahan D., Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 86:1996;353-364.
53. Harari P.M., Huang S.M. Radiation response modification following molecular inhibition of epidermal growth factor receptor signaling. Semin Radiat Oncol. 11:2001;281-289.
54. Haroon Z.A., Raleigh J.A., Greenberg C.S., Dewhirst M.W. Early wound healing exhibits cytokine surge without evidence of hypoxia. Ann Surg. 231:2000;137-147.
55. 2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med. 3:1997;177-182.
56. Henk J.M. Late results of a trial of hyperbaric oxygen and radiotherapy in head and neck cancer: a rationale for hypoxic cell sensitizers? Int J Radiat Oncol Biol Phys. 12:1986;1339-1341.
57. Höckel M., Schlenger K., Aral B., Mitze M., Schaffer U., Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 56:1996;4509-4515.
58. Höckel M., Schlenger K., Höckel S., Vaupel P. Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Res. 59:1999;4525-4528.
59. Höckel M., Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 93:2001;266-276.
60. Horak E.R., Leek R., Klenk N., et al. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet. 340:1992;1120-1124.
61. Hoskin P.J., Saunders M.I., Dische S. Hypoxic radiosensitizers in radical radiotherapy for patients with bladder carcinoma: hyperbaric oxygen, misonidazole, and accelerated radiotherapy, carbogen, and nicotinamide. Cancer. 86:1999;1322-1328.
62. Ivanov S.V., Kuzmin I., Wei M.H., et al. Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes. Proc Natl Acad Sci USA. 95:1998;12596-12601.
63. Ivanov S., Liao S.Y., Ivanova A., et al. Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol. 158:2001;905-919.
64. Jaeger T.M., Weidner N., Chew K., et al. Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer. J Urol. 154:1995;69-71.
65. Jain R.K. Determinants of tumor blood flow: a review. Cancer Res. 48:1988;2641-2658.
66. Jain R.K. Transport of molecules, particles, and cells in solid tumors. Annu Rev Biomed Eng. 1:1999;241-263.
67. Jenkins W.T., Evans S.M., Koch C.J. Hypoxia and necrosis in Rat 9L glioma and Morris 7777 hepatoma tumors: comparative measurements using EF5 binding and the Eppendorf needle electrode. Int J Radiat Oncol Biol. Phys. 46:2000;1005-1017.
68. Jenssen N., Boysen M., Kjaerheim A., Bryne M. Low vascular density indicates poor response to radiotherapy in small glottic carcinomas. Pathol Res Pract. 192:1996;1090-1094.
69. Kaanders J.H.A.M., Pop L.A.M., Marres H.A.M., et al. ARCON: experience in 215 patients with advanced head and neck cancer. Int J Radiat Oncol Biol Phys. 52:2002;769-778.
70. Kaanders J.H.A.M., Wijffels K.I.E.M., Marres H.A.M., et al. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res. 62:2002;7066-7074.
71. Kallman R.F., Dorie M.J. Tumor oxygenation and reoxygenation during radiation therapy: their importance in predicting tumor response. Int J Radiat Oncol Biol Phys. 12:1986;681-685.
72. Kawamura T., Kusakabe T., Sugino T., et al. Expression of glucose transporter-1 in human gastric carcinoma: association with tumor aggressiveness, metastasis, and patient survival. Cancer. 92:2001;634-641.
73. Kennedy A.S., Raleigh J.A., Perez G.M., et al. Proliferation and hypoxia in human squamous cell carcinoma of the cervix: first report of combined immunohistochemical assays. Int J Radiat Oncol Biol Phys. 37:1997;897-905.
74. Koch C.J., Evans S.M., Lord E.M. Oxygen dependence of cellular uptake of EF5 [2-(2-nitro-1H-imidazol-1-yl)-2-(2,2,3,3,3-pentafluoropropyl) acetamide]:analysis of drug adducts by fluorescent antibodies vs bound radioactivity. Br J Cancer. 72:1995;869-874.
75. Konerding M.A., Miodonski A.J., Lametschwandtner A. Microvascular corrosion casting in the study of tumor vascularity: a review. Scanning Microsc. 9:1995;1233-1243.
76. Konerding M.A., Malkusch W., Klapthor B., et al. Evidence for characteristic vascular patterns in solid tumours: quantitative studies using corrosion casts. Br J Cancer. 80:1999;724-732.
77. Koukourakis M.I., Giatromanolaki A., Sivridis E., Fezoulidis I. Cancer vascularization: implications in radiotherapy? Int J Radiat Oncol Biol Phys. 48:2000;545-553.
78. Koukourakis M.I., Giatromanolaki A., Sivridis E., et al. Hypoxia-regulated carbonic anhydrase-9 (CA9) relates to poor vascularization and resistance of squamous cell head and neck cancer to chemoradiotherapy. Clin Cancer Res. 7:2001;3399-3403.
79. Krishna M.C., English S., Yamada K., et al. Overhauser enhanced magnetic resonance imaging for tumor oximetry: coregistration of tumor anatomy and tissue oxygen concentration. Proc Natl Acad Sci USA. 99:2002;2216-2221.
80. Kropveld A., Slootweg P.J., Blankenstein M.A., Terhaard C.H.J., Hordijk G.J. Ki-67 and p53 in T2 laryngeal cancer. Laryngoscope. 108:1998;1548-1552.
81. Lal A., Peters H., St Croix B., et al. Transcriptional response to hypoxia in human tumors. J Natl Cancer Inst. 93:2001;1337-1343.
82. Lera J., Lara P.C., Perez S., Cabrera J.L., Santana C. Tumor proliferation, p53 expression, and apoptosis in laryngeal carcinoma. Cancer. 15:1998;2493-2501.
83. Levine E.L., Renehan A., Gossiel R., et al. Apoptosis, intrinsic radiosensitivity and prediction of radiotherapy response in cervical carcinoma. Radiother Oncol. 37:1995;1-9.
84. Ljungkvist A.S.E., Bussink J., Rijken P.F.J.W., Raleigh J.A., Denekamp J., van der Kogel A.J. Changes in tumor hypoxia measured with a double hypoxic marker technique. Int J Radiat Oncol Biol Phys. 48:2000;1529-1538.
85. Ljungkvist A.S.E., Bussink J., Rijken P.F.J.W., Kaanders J.H.A.M., van der Kogel A.J., Denekamp J. Vascular architecture, hypoxia, and proliferation in the first passage of xenografts of human head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys. 54:2002;215-228.
86. Loncaster J.A., Harris A.L., Davidson S.E., et al. Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res. 61:2001;6394-6399.
87. Lyng H., Sundfor K., Rofstad E.K. Changes in tumor oxygen tension during radiotherapy of uterine cervical cancer: relationships to changes in vascular density, cell density, and frequency of mitosis and apoptosis. Int J Radiat Oncol Biol Phys. 46:2000;935-946.
88. Macchiarini P., Fontanini G., Hardin M.J., Squartini F., Angeletti C.A. Relation of neovascularisation to metastasis of non-small-cell lung cancer. Lancet. 340:1992;145-146.
89. Mason R.P., Constantinescu A., Hunjan S., et al. Regional tumor oxygenation and measurement of dynamic changes. Radiat Res. 152:1999;239-249.
90. Matthews N.E., Adams M.A., Maxwell L.R., Gofton T.E., Graham C.H. Nitric oxide-mediated regulation of chemosensitivity in cancer cells. J Natl Cancer Inst. 93:2001;1879-1885.
91. Maxwell P.H., Wiesener M.S., Chang G.W., et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 399:1999;271-275.
92. Mellanen P., Minn H., Grenman R., Harkonen P. Expression of glucose transporters in head-and-neck tumors. Int J Cancer. 56:1994;622-629.
93. Nordsmark M., Overgaard M., Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol. 41:1996;31-39.
94. Nordsmark M., Hoyer M., Keller J., Nielsen O.S., Jensen O.M., Overgaard J. The relationship between tumor oxygenation and cell proliferation in human soft tissue sarcomas. Int J Radiat Oncol Biol Phys. 35:1996;701-708.
95. Nordsmark M., Overgaard J. A confirmatory prognostic study on oxygenation status and loco-regional control in advanced head and neck squamous cell carcinoma treated by radiation therapy. Radiother Oncol. 57:2000;39-43.
96. Nordsmark M., Loncaster J., Chou S.C., et al. Invasive oxygen measurement and pimonidazole labeling in human cervix carcinoma. Int J Radiat Oncol Biol Phys. 49:2001;581-586.
97. Nordsmark M., Alsner J., Keller J., et al. Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations. Br J Cancer. 84:2001;1070-1075.
98. Nylander K., Schildt E.-B., Eriksson M., Roos G. PCNA. Ki-67, p53, bcl-2 and prognosis in intraoral squamous cell carcinoma of the head and neck. Anal Cell Pathol. 14:1997;101-110.
99. Olive P.L. Radiation-induced reoxygenation in the SCCVII murine tumour: evidence for a decrease in oxygen consumption and an increase in tumour perfusion. Radiother Oncol. 32:1994;37-46.
100. Olive P.L., Durand R.E., Raleigh J.A., Luo C., Aquino-Parsons C. Comparison between the comet assay and pimonidazole binding for measuring tumor hypoxia. Br J Cancer. 83:2000;1525-1531.
101. Olive P.L., Aquino-Parsons C., MacPhail S.H., et al. Carbonic anhydrase 9 as an endogenous marker for hypoxic cells in cervical cancer. Cancer Res. 61:2001;8924-8929.
102. Overgaard J., Hansen H.S., Overgaard M., et al. A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85. Radiother Oncol. 46:1998;135-146.
103. Parkkila S., Rajaniemi H., Parkkila A.K., et al. Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro. Proc Natl Acad Sci USA. 97:2000;2220-2224.
104. Pitson G., Fyles A., Milosevic M., Wylie J., Pintilie M., Hill R. Tumor size and oxygenation are independent predictors of nodal diseases in patients with cervix cancer. Int J Radiat Oncol Biol Phys. 51:2001;699-703.
105. Raleigh J.A., Zeman E.M., Calkins D.P., McEntee M.C., Thrall D.E. Distribution of hypoxia and proliferation associated markers in spontaneous canine tumors. Acta Oncol. 34:1995;345-349.
106. Raleigh J.A., Calkins-Adams D.P., Rinker L.H., et al. Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res. 58:1998;3765-3768.
107. Raleigh J.A., Chou S.C., Arteel G.E., Horsman M.R. Comparisons among pimonidazole binding, oxygen electrode measurements, and radiation response in C3H mouse tumors. Radiat Res. 151:1999;580-589.
108. Raleigh J.A., Chou S.C., Calkins-Adams D.P., Ballenger C.A., Novotny D.B., Varia M.A. A clinical study of hypoxia and metallothionein protein expression in squamous cell carcinomas. Clin Cancer Res. 6:2000;855-862.
109. Reed J.C. Dysregulation of apoptosis in cancer. J Clin Oncol. 17:1999;2941-2953.
110. Rijken P.F.J.W., Bernsen H.J.J.A., Peters J.P.W., Hodgkiss R.J., Raleigh J.A., van der Kogel A.J. Spatial relationship between hypoxia and the (perfused) vascular network in a human glioma xenograft: a quantitative multi-parameter analysis. Int J Radiat Oncol Biol Phys. 48:2000;571-582.
111. Rischin D., Peters L., Hicks R., Phase I., et al. trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol. 19:2001;535-542.
112. Robert F., Ezekiel M.P., Spencer S.A., Phase I., et al. study of anti-epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol. 19:2001;3234-3243.
113. Rofstad E.K. Microenvironment-induced cancer metastasis. Int J Radiat Biol. 76:2000;589-605.
114. Rojas A., Hirst V.K., Calvert A.S., Johns H. Carbogen and nicotinamide as radiosensitizers in a murine mammary carcinoma using conventional and accelerated radiotherapy. Int J Radiat Oncol Biol Phys. 34:1996;357-365.
115. 2 histography in patients with advanced head and neck cancer. Radiother Oncol. 57:2000;31-37.
116. Saarnio J., Parkkila S., Parkkila A.K., et al. Immunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase. MN/CA IX, with potential value as a marker of cell proliferation. Am J Pathol. 153:1998;279-285.
117. Sauter E.R., Nesbit M., Watson J.C., Klein-Szanto A., Litwin S., Herlyn M. Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res. 5:1999;775-782.
118. Schmaltz C., Hardenbergh P.H., Wells A., Fisher D.E. Regulation of proliferation-survival decisions during tumor cell hypoxia. Mol Cell Biol. 18:1998;2845-2854.
119. Secomb T.W., Hsu R., Ong E.T., Gross J.F., Dewhirst M.W. Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncol. 34:1995;313-316.
120. Selvaggi G, Scagliotti GV, Torri V. Her-2/neu overexpression in radically resected non-small cell lung cancer (NSCLC): impact on long-term survival. Cancer 2002;94:2669-74 .
121. Semenza G.L. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol. 88:2000;1474-1480.
122. Semenza G.L. Hypoxia, clonal selection and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol. 35:2000;71-103.
123. Sheridan M.T., Cooper R.A., West C.M. A high ratio of apoptosis to proliferation correlates with improved survival after radiotherapy for cervical adenocarcinoma. Int J Radiat Oncol Biol Phys. 44:1999;507-512.
124. Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 359:1992;843-845.
125. Sittel C., Ruiz S., Volling P., Kvasnicka H.M., Jungehülsing M., Eckel H.E. Prognostic significance of Ki-67 (MIB1). PCNA and p53 in cancer of the oropharynx and oral cavity. Oral Oncol. 35:1999;583-589.
126. Sittel C., Eckel H.E., Damm M., von Pritzbuer E., Kvasnicka H.M. Ki-67 (MIB1), p53 and Lewis-X (LeuM1) as prognostic factors of recurrence in T1 and T2 laryngeal carcinoma. Laryngoscope. 110:2000;1012-1017.
127. Sly W.S., Hu P.Y. Human carbonic anhydrases and carbonic anhydrase deficiencies. Annu Rev Biochem. 64:1995;375-401.
128. Smith E., Stratford I.J., Adams G.E. Cytotoxicity of adriamycin on aerobic and hypoxic Chinese hamster V79 cells in vitro. Br J Cancer. 42:1980;568-573.
129. Stadler P., Becker A., Feldmann H.J., et al. Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Oncol Biol Phys. 44:1999;749-754.
130. Sundfor K., Lyng H., Rofstad E.K. Tumor hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix. Cancer Res. 58:1998;3598-3602.
131. Talks K.L., Turley H., Gatter K.C., et al. The expression and distribution of the hypoxia-inducible factor HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol. 157:2000;411-421.
132. Thomlinson R.H., Gray L.H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer. 9:1955;539-549.
133. Tsang R.W., Fyles A.W., Li Y., et al. Tumor proliferation and apoptosis in human uterine cervix carcinoma I: correlations between variables. Radiother Oncol. 50:1999;85-92.
134. Tsang R.W., Wong C.S., Fyles A.W., et al. Tumour proliferation and apoptosis in human uterine cervix carcinoma II: correlations with clinical outcome. Radiother Oncol. 50:1999;93-101.
135. Tsang R.W., Fyles A.W., Milosevic M., et al. Interrelationship of proliferation and hypoxia in carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 46:2000;95-99.
136. Turner J.R., Odze R.D., Crum C.P., Resnick M.B. MN antigen expression in normal, preneoplastic, and neoplastic esophagus: a clinicopathological study of a new cancer-associated biomarker. Hum Pathol. 28:1997;740-744.
137. Ullrich A., Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 61:1990;203-212.
138. Vermeulen P.B., van den Eynden G.G., Huget P., et al. Prospective study of intratumoral microvessel density, p53 expression and survival in colorectal cancer. Br J Cancer. 79:1999;316-322.
139. Volm M., Koomagi R. Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. Anticancer Res. 20:2000;1527-1533.
140. von Pawel J., von Roemeling R., Gatzemeier U., et al. Tirapazamine plus cisplatin versus cisplatin in advanced non-small-cell lung cancer: A report of the international CATAPULT I study group. Cisplatin and tirapazamine in subjects with advanced previously untreated non-small-cell lung tumors. J Clin Oncol. 18:2000;1351-1359.
141. Vukovic V., Haugland H.K., Nicklee T., Morrison A.J., Hedley D.W. Hypoxia-inducible factor-1α is an intrinsic marker for hypoxia in cervical cancer xenografts. Cancer Res. 61:2001;7394-7398.
142. Walenta S., Snyder S., Haroon Z.A., et al. Tissue gradients of energy metabolites mirror oxygen tension gradients in a rat mammary carcinoma model. Int J Radiat Oncol Biol Phys. 51:2001;840-848.
143. Watson E.R., Halnan K.E., Dische S., et al. Hyperbaric oxygen and radiotherapy: a Medical Research Council trial in carcinoma of the cervix. Br J Radiol. 51:1978;879-887.
144. Watt F.M., Green H. Involucrin synthesis is correlated with cell size in human epidermal cultures. J Cell Biol. 90:1981;738-742.
145. Webster L., Hodgkiss R.J., Wilson G.D. Simultaneous triple staining for hypoxia, proliferation, and DNA content in murine tumours. Cytometry. 21:1995;344-351.
146. Weidner N., Semple J.P., Welch W.R., Folkman J. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med. 324:1991;1-8.
147. Wheeler J.A., Stephens L.C., Tornos C., et al. ASTRO Research Fellowship: apoptosis as a predictor of tumor response to radiation in stage IB cervical carcinoma. American Society for Therapeutic Radiology and Oncology. Int J Radiat Oncol Biol Phys. 32:1995;1487-1493.
148. Wiesener M.S., Munchenhagen P.M., Berger I., et al. Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1alpha in clear cell renal carcinomas. Cancer Res. 61:2001;5215-5222.
149. Wijffels K.I.E.M., Kaanders J.H.A.M., Rijken P.F.J.W., et al. Vascular architecture and hypoxic profiles in human head and neck squamous cell carcinomas. Br J Cancer. 83:2000;674-683.
150. Wijffels K.I.E.M., Kaanders J.H.A.M., Marres H.A.M., et al. Patterns of proliferation related to vasculature in human head and neck carcinomas before and after transplantation in nude mice. Int J Radiat Oncol Biol Phys. 51:2001;1346-1353.
151. Wilson G.D., Dische S., Saunders M.I. Studies with bromodeoxyuridine in head and neck cancer and accelerated radiotherapy. Radiother Oncol. 36:1995;189-197.
152. Wilson G.D., Saunders M.I., Dische S., Richman P.I., Daley F.M., Bentzen S.M. bcl-2 expression in head and neck cancer: an enigmatic prognostic marker. Int J Radiat Oncol Biol Phys. 49:2001;435-441.
153. Wilson R.E., Keng P.C., Sutherland R.M. Drug resistance in Chinese hamster ovary cells during recovery from severe hypoxia. J Natl Cancer Inst. 81:1989;1235-1240.
154. Withers H.R., Taylor J.M., Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol. 27:1988;131-146.
155. Wouters B.G., Brown J.M. Cells at intermediate oxygen levels can be more important than the 'hypoxic fraction' in determining tumor response to fractionated radiotherapy. Radiat Res. 147:1997;541-550.
156. Wykoff C.C., Beasley N.J.P., Watson P.H., et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 60:2000;7075-7083.
157. Wykoff C.C., Beasley N., Watson P.H., et al. Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast. Am J Pathol. 158:2001;1011-1019.
158. Younes M., Brown R.W., Stephenson M., Gondo M., Cagle P.T. Overexpression of Glut-1 and Glut-3 in stage I non-small-cell lung carcinoma is associated with poor survival. Cancer. 80:1997;1046-1051.
159. Younes M., Juarez D., Lechago L.V., Lerner S.P. Glut 1 expression in transitional cell carcinoma of the urinary bladder is associated with poor patient survival. Anticancer Res. 21:2001;575-578.
160. Zagzag D., Zhong H., Scalzitti J.M., Laughner E., Simons J.W., Semenza G.L. Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer. 88:2000;2606-2618.
161. Zhong H., de Marzo A.M., Laughner E., et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res. 59:1999;5830-5835.