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. 2000 Feb 21;82(6):1177–1182. doi: 10.1054/bjoc.1999.1059

Pretreatment apoptosis in carcinoma of the cervix correlates with changes in tumour oxygenation during radiotherapy

M T Sheridan 1, C M L West 1, R A Cooper 1, I J Stratford 3, J P Logue 3, S E Davidson 2, R D Hunter 2
PMCID: PMC2363353  PMID: 10735502

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

Keywords: cervix carcinoma, apoptosis, hypoxia, reoxygenation, radiotherapy

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Selected References

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  1. Badib A. O., Webster J. H. Changes in tumor oxygen tension during radiation therapy. Acta Radiol Ther Phys Biol. 1969 Jun;8(3):247–257. doi: 10.3109/02841866909134455. [DOI] [PubMed] [Google Scholar]
  2. Brown J. M., Giaccia A. J. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res. 1998 Apr 1;58(7):1408–1416. [PubMed] [Google Scholar]
  3. Cooper R. A., West C. M., Logue J. P., Davidson S. E., Miller A., Roberts S., Statford I. J., Honess D. J., Hunter R. D. Changes in oxygenation during radiotherapy in carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 1999 Aug 1;45(1):119–126. doi: 10.1016/s0360-3016(99)00093-0. [DOI] [PubMed] [Google Scholar]
  4. Fyles A. W., Milosevic M., Pintilie M., Hill R. P. Cervix cancer oxygenation measured following external radiation therapy. Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):751–753. doi: 10.1016/s0360-3016(98)00307-1. [DOI] [PubMed] [Google Scholar]
  5. Fyles A. W., Milosevic M., Wong R., Kavanagh M. C., Pintilie M., Sun A., Chapman W., Levin W., Manchul L., Keane T. J. Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol. 1998 Aug;48(2):149–156. doi: 10.1016/s0167-8140(98)00044-9. [DOI] [PubMed] [Google Scholar]
  6. Graeber T. G., Osmanian C., Jacks T., Housman D. E., Koch C. J., Lowe S. W., Giaccia A. J. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996 Jan 4;379(6560):88–91. doi: 10.1038/379088a0. [DOI] [PubMed] [Google Scholar]
  7. Graeber T. G., Peterson J. F., Tsai M., Monica K., Fornace A. J., Jr, Giaccia A. J. 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. 1994 Sep;14(9):6264–6277. doi: 10.1128/mcb.14.9.6264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Grasl-Kraupp B., Ruttkay-Nedecky B., Koudelka H., Bukowska K., Bursch W., Schulte-Hermann R. In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology. 1995 May;21(5):1465–1468. doi: 10.1002/hep.1840210534. [DOI] [PubMed] [Google Scholar]
  9. Hockel 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. 1996 Oct 1;56(19):4509–4515. [PubMed] [Google Scholar]
  10. Höckel M., Knoop C., Schlenger K., Vorndran B., Baussmann E., Mitze M., Knapstein P. G., Vaupel P. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol. 1993 Jan;26(1):45–50. doi: 10.1016/0167-8140(93)90025-4. [DOI] [PubMed] [Google Scholar]
  11. Kerr J. F., Wyllie A. H., Currie A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239–257. doi: 10.1038/bjc.1972.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kim C. Y., Tsai M. H., Osmanian C., Graeber T. G., Lee J. E., Giffard R. G., DiPaolo J. A., Peehl D. M., Giaccia A. J. Selection of human cervical epithelial cells that possess reduced apoptotic potential to low-oxygen conditions. Cancer Res. 1997 Oct 1;57(19):4200–4204. [PubMed] [Google Scholar]
  13. Lartigau E., Lusinchi A., Weeger P., Wibault P., Luboinski B., Eschwege F., Guichard M. Variations in tumour oxygen tension (pO2) during accelerated radiotherapy of head and neck carcinoma. Eur J Cancer. 1998 May;34(6):856–861. doi: 10.1016/s0959-8049(97)10172-1. [DOI] [PubMed] [Google Scholar]
  14. Levine E. L., Renehan A., Gossiel R., Davidson S. E., Roberts S. A., Chadwick C., Wilks D. P., Potten C. S., Hendry J. H., Hunter R. D. Apoptosis, intrinsic radiosensitivity and prediction of radiotherapy response in cervical carcinoma. Radiother Oncol. 1995 Oct;37(1):1–9. doi: 10.1016/0167-8140(95)01622-n. [DOI] [PubMed] [Google Scholar]
  15. Lyng H., Sundfør K., Tanum G., Rofstad E. K. Oxygen tension in primary tumours of the uterine cervix and lymph node metastases of the head and neck. Adv Exp Med Biol. 1997;428:55–60. doi: 10.1007/978-1-4615-5399-1_9. [DOI] [PubMed] [Google Scholar]
  16. Meyn R. E., Stephens L. C., Ang K. K., Hunter N. R., Brock W. A., Milas L., Peters L. J. Heterogeneity in the development of apoptosis in irradiated murine tumours of different histologies. Int J Radiat Biol. 1993 Nov;64(5):583–591. doi: 10.1080/09553009314551801. [DOI] [PubMed] [Google Scholar]
  17. Milosevic M. F., Fyles A. W., Wong R., Pintilie M., Kavanagh M. C., Levin W., Manchul L. A., Keane T. J., Hill R. P. Interstitial fluid pressure in cervical carcinoma: within tumor heterogeneity, and relation to oxygen tension. Cancer. 1998 Jun 15;82(12):2418–2426. doi: 10.1002/(sici)1097-0142(19980615)82:12<2418::aid-cncr16>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  18. Moulder J. E., Rockwell S. Hypoxic fractions of solid tumors: experimental techniques, methods of analysis, and a survey of existing data. Int J Radiat Oncol Biol Phys. 1984 May;10(5):695–712. doi: 10.1016/0360-3016(84)90301-8. [DOI] [PubMed] [Google Scholar]
  19. Rupnow B. A., Murtha A. D., Alarcon R. M., Giaccia A. J., Knox S. J. Direct evidence that apoptosis enhances tumor responses to fractionated radiotherapy. Cancer Res. 1998 May 1;58(9):1779–1784. [PubMed] [Google Scholar]
  20. 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. 1999 Jun 1;44(3):507–512. doi: 10.1016/s0360-3016(99)00081-4. [DOI] [PubMed] [Google Scholar]
  21. Stadler P., Feldmann H. J., Creighton C., Kau R., Molls M. Changes in tumor oxygenation during combined treatment with split-course radiotherapy and chemotherapy in patients with head and neck cancer. Radiother Oncol. 1998 Aug;48(2):157–164. doi: 10.1016/s0167-8140(98)00032-2. [DOI] [PubMed] [Google Scholar]
  22. Tsang R. W., Wong C. S., Fyles A. W., Levin W., Manchul L. A., Milosevic M., Chapman W., Li Y. Q., Pintilie M. Tumour proliferation and apoptosis in human uterine cervix carcinoma II: correlations with clinical outcome. Radiother Oncol. 1999 Jan;50(1):93–101. doi: 10.1016/s0167-8140(98)00119-4. [DOI] [PubMed] [Google Scholar]
  23. Vaupel P., Schlenger K., Knoop C., Höckel M. Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res. 1991 Jun 15;51(12):3316–3322. [PubMed] [Google Scholar]
  24. Wheeler J. A., Stephens L. C., Tornos C., Eifel P. J., Ang K. K., Milas L., Allen P. K., Meyn R. E., Jr 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. 1995 Jul 30;32(5):1487–1493. doi: 10.1016/0360-3016(95)00156-s. [DOI] [PubMed] [Google Scholar]

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