Abstract
A relationship between hypoxia and apoptosis has been identified in vitro and in experimental tumours. The aim of this study was to investigate the relationship between apoptosis, hypoxia and the change in oxygenation during radiotherapy in human squamous cell carcinoma of the cervix. Forty-two patients with locally advanced disease underwent pretreatment evaluation of tumour oxygenation using an Eppendorf computerized microneedle electrode. Twenty-two of these patients also had a second evaluation of tumour oxygenation after receiving 40–45 Gy external beam radiotherapy. Paraffin-embedded histological sections were obtained from random pretreatment biopsies for all 42 patients. Apoptotic index (AI) was quantified by morphology on TUNEL stained sections. No correlation was found between pretreatment measures of AI and either the median pO2(r = 0.12, P = 0.44) or percentage of values < 5 mmHg (r = –0.02, P = 0.89). A significant positive correlation was found between AI and the change in tumour oxygenation (ratio of pre:post-treatment % values < 5 mmHg) following radiotherapy (r = 0.61, P = 0.002). The lack of correlation between apoptosis and hypoxia may occur because the Eppendorf measures both acute and chronic hypoxia, and the relative ability of acute hypoxia to induce apoptosis is unknown. These results indicate that cell death via apoptosis may be a mechanism of tumour reoxygenation during radiotherapy. © 2000 Cancer Research Campaign
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References
Badib AO and Webster JH (1969) Changes in tumour oxygen tension during radiation therapy. Acta Radiol Ther Physics Biol 8: 247–257
Brown MJ and Giaccia AJ (1998) The unique physiology of solid tumours: opportunities (and problems) for cancer therapy. Cancer Res 58: 1408–1416
Cooper RA, West CML, Logue JP, Davidson SE, Miller A, Roberts S, Stratford IJ, Honess DJ and Hunter RD (1999) Changes in oxygenation during radiotherapy in carcinoma of the cervix. Int J Radiat Oncol Biol Phys 45: 119–126
Fyles AW, Milosevic M, Wong R, Kavanagh M, Pintilie M, Sun A, Chapman W, Levin W, Manchul L, Keane TJ and Hill RP (1998 a) Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol 48: 149–156
Fyles AW, Milosevic M, Pintilie M and Hill RP (1998 b) Cervix cancer oxygenation measured following external radiation therapy. Int J Radiat Oncol Biol Phys 42: 751–753
Graeber TG, Peterson JF, Tsai M, Monica K, Fornace AJ and Giaccia AJ (1994) Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol 14: 6264–6277
Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW and Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379: 88–91
Grasl-Kraupp B, Ruttkay-Nedecky B, Koudelka H, Bukowska K, Bursch W and Schulte-Hermann R (1995) In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology 21: 1465–1468
Höckel M, Knoop C, Schlenger K, Vorndran B, Baußmann E, Mitze M, Knapstein PG and Vaupel P (1993) Intratumoral pO2predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 26: 45–50
Höckel M, Schlenger K, Aral B, Mitze M, Schäffer U and Vaupel P (1996) Association between tumour hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56: 4509–4515
Horsman MR and Overgaard J (1997) The oxygen effectIn: Basic Clinical Radiobiology, Steel G (ed), pp. 132–140, Arnold: London
Kerr JFR, Wyllie AH and Currie AR (1972) Apoptosis: a basic biological phenomenon with wide ranging implications in tissue kinetics. Br J Cancer 26: 239–257
Kim CY, Tsai MH, Osmanian C, Greaber TG, Lee JE, Giffard RG, DiPaolo JA, Peehl DM and Giaccia AJ (1997) Selection of human cervical epithelial cells that possess reduced apoptotic potential to low-oxygen conditions. Cancer Res 57: 4200–4204
Lartigau E, Luisinchi A, Weeger P, Wibault P, Luboinski B, Eschwege F and Guichard M (1998) Variations in tumour oxygen tension (pO2) during accelerated radiotherapy of head and neck carcinoma. Eur J Cancer 34: 856–861
Levine EL, Renehan A, Gossiel R, Davidson SE, Roberst SA, Chadwick C, Wilks DP, Potten CS, Hendry JH, Hunter RD and West CML (1995) Apoptosis, intrinsic radiosensitivity and prediction of radiotherapy response in cervical carcinoma. Radiother Oncol 37: 1–9
Lyng H, Sundfør K, Tanum G and Rofstad EK (1997) Oxygen tension in primary tumours of the uterine cervix and lymph node metastases of the head and neckIn: Oxygen Transport to Tissue XIX, Harrison Deply (eds), pp. 55–60, Plenum Press: New York
Meyn RE, Milas L, Story MD, Ang KK, Tomasovic SP and Stephens C (1992) Programmed cell death in response of normal and tumour tissue to radiation. Cancer Bull 44: 80–85
Meyn RE, Stephens LC, Ang KK, Hunter NR, Brock WA, Milas L and Peters LJ (1993) Heterogeneity in the development of apoptosis in irradiated murine tumours of different histologies. Int J Radiat Biol 64: 583–591
Milas L, Günderoth M and Peters LJ (1995) Drug and radiation-induced apoptosis as a mechanism of reoxygenationIn: Tumour Oxygenation, Vaupel PW, Kelleher DK and Günderoth M (eds), pp. 165–173, Gustav Fisher Verlag: Stuttgart
Milosevic MF, Fyles AW, Wong R, Pintilie M, Kavanagh M-C, Levin W, Manchul LA, Keane TJ and Hill RP (1998) Interstitial fluid pressure in cervical carcinoma. Cancer 82: 2418–2426
Moulder JE and Rockwell S (1984) Hypoxic fractions of solid tumours: experimental techniques, methods of analysis, and a survey of existing data. Int J Radiat Oncol Biol Phys 10: 695–712
Overgaard J and Horsman MR (1997) Overcoming hypoxic cell radioresistanceIn: Basic Clinical Radiology, GG Steel (Ed), pp 141–151, Arnold: London
Rupnow BA, Murtha AD, Alarcon RM, Giaccia AJ and Knox SJ (1998) Direct evidence that apoptosis enhances tumour responses to fractionated radiotherapy. Cancer Res 58: 1779–1784
Sheridan MT, Cooper RA and West CML (1999) A high ratio of apoptosis to proliferation correlates with improved survival after radiotherapy for cervical adenocarcinoma. Int J Radiat Oncol Biol Phys 44: 507–512
Stadler P, Feldman HJ, Creighton C, Kau R and Molls M (1998) Changes in tumour oxygenation during combined treatment with split-course radiotherapy and chemotherapy in patients with head and neck cancer. Radiother Oncol 48: 157–164
Tsang RW, Fyles AW, Li Y, Rajaraman MM, Chapman W, Pintilie M and Wong S (1999) Tumor proliferation and apoptosis in human uterine cervix carcinoma II: correlations with clinical outcome. Radiother Oncol 50: 93–101
Vaupel P, Schlenger K, Knoop C and Höckel M (1991) Oxygenation of human tumours: evaluation of tissue oxygen distribution in breast cancers by computerised O2tension measurements. Cancer Res 51: 3316–3322
Wheeler JA, Stephens LC, Tornos C, Eifel PJ, Ang KK, Milas L, Allen PK and Meyn RE (1995) ASTRO research fellowship: apoptosis as a predictor of tumor response to radiation in stage IB cervical carcinoma. Int J Radiat Oncol Biol Phys 32: 1487–1493
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Sheridan, M., West, C., Cooper, R. et al. Pretreatment apoptosis in carcinoma of the cervix correlates with changes in tumour oxygenation during radiotherapy. Br J Cancer 82, 1177–1182 (2000). https://doi.org/10.1054/bjoc.1999.1059
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DOI: https://doi.org/10.1054/bjoc.1999.1059
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