Summary
A potential usefulness of micronucleus assay for prediction of tumour radiosensitivity has been tested in 64 patients with advanced stage (II B–IV B) cervical carcinoma treated by radiotherapy. The study of cellular radiosensitivity in vitro was conducted in parallel with the study of cellular damage after tumour irradiation in vivo. Radiosensitivity of in vitro cultured primary cells isolated from tumour biopsies taken before radiotherapy was evaluated using cytokinesis-block micronucleus assay. Frequency of micronuclei per binucleated cell (MN/BNC) at 2 Gy was used as a measure of radiosensitivity. Radiation sensitivity in vivo was expressed as per cent increment of micronucleus frequency in cells isolated from biopsy taken after 20 Gy (external irradiation, 10 × 2 Gy) over the pre-treatment spontaneous micronucleus level and was called MN20. Very low correlation (r = 0.324) was observed between micronucleus frequency in vitro and in vivo. Although micronucleus frequency at 2 Gy differed widely between tumours evaluated (mean MN/BNC was 0.224; range 0.08–0.416), no significant correlation was observed between this parameter and clinical outcome. The average increment of micronucleus frequency after 20 Gy amounted to 193% of spontaneous level (range 60–610%) and was independent of spontaneous micronucleation before radiotherapy. In contrast to in vitro results, these from in vivo assay seem to have a predictive value for radiotherapy of cervix cancer. The micronucleus increment in vivo that reached at least 117.5% of pretreatment value (first quartile for MN20 data set) correlated significantly with better tumour local control (P < 0.008) and overall survival (P < 0.045). Our results suggest that evaluation of increment of micronucleus frequency during radiotherapy (after fixed tested dose of 20 Gy) offers a potentially valuable approach to predicting individual radioresponsiveness and may be helpful for individualization of treatment strategy in advanced stage cervical cancer.
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References
Bakker, P. J. M., Tukker, L. J., Stap, J., Veenhof, C. H. N. & Aten, J. A. (1993). Micronuclei expression in tumours as a test for radiation sensitivity. Radiother Oncol 26: 69–72.
Bush, C. & McMillan, T. J. (1993). Micronucleus formation in human tumour cells: lack of correlation with radiosensitivity. Br J Cancer 67: 102–106.
Champion, A. R., Hanson, J. A., Court, J. B. & Venables, S. E. (1995). The micronucleus assay: an evaluation of its use in determining radiosensitivity in vitro. Mutagenesis 10: 203–208.
Davidson, S. E., West, C. M. L., Roberts, S. A., Hendry, J. H. & Hunter, R. D. (1990). Radiosensitivity testing of primary cervical carcinoma; evaluation of intra- and inter-tumour heterogeneity. Radiother Oncol 18: 349–359.
Fertil, B. & Malaise, E. P. (1985). Intrinsic radiosensitivity of human cell lines is correlated with radioresponsiveness of human tumors. Analysis of 101 published survival curves. Int J Radiat Oncol Biol Phys 11: 1699–1707.
Girynsky, T., Lubin, R., Pignon, J. P., Chavaudra, N., Gazean, J., Dubray, B., Cosset, J. M., Socie, G. & Fertil, B. (1992). Predictive value of in vitro radiosensitivity parameters in head and neck cancers and cervical carcinomas: preliminary correlations with local control and overall survival. Int J Radiat Oncol Biol Phys 25: 3–7.
Heddle, J. A. & Carrano, A. V. (1977). The DNA content in micronuclei induced in mouse bone marrow by gamma irradiation: evidence that micronuclei arise from acentric chromosomal fragments. Mutat Res 44: 63–69.
Johansen, J., Streffer, C., Fuhrmann, C., Bentzen, S. M., Stausbøl-Grøn, B., Overgaard, M. & Overgaard, J. (1998). Radiosensitivity of normal fibroblasts from breast cancer patients assessed by the micronucleus and colony assays. Int J Radiat Biol 73: 671–678.
Mariya, Y., Streffer, C., Fuhrmann, C. & Wojcik, A. (1997). Correlation of radiation-induced micronucleus frequency with clonogenic survival in cells of one diploid and two tetraploid murine tumor cell lines of the same origin. Radiat Res 147: 29–34.
Midander, J. & Revesz, L. (1980). The frequency of micronuclei as a measure of cell survival in irradiated cell populations. Int J Radiat Biol 38: 237–242.
Schwartz, J. L., Mustafi, R., Beckett, M. A., Czyz·ewski, E. A., Farhangi, E., Grdina, D. J., Rotmensch, R. & Weichselbaum, R. R. (1991). Radiation-induced DNA double-strand break frequencies in human squamous cell lines of different radiation sensitivities. Int J Radiat Biol 59: 1341–1352.
Schwartz, J. L., Mustafi, R., Beckett, M. A. & Weichselbaum, R. R. (1996). DNA double-strand break rejoining rates, inherent radiation sensitivity and human tumour response to radiotherapy. Br J Cancer 74: 37–42.
Shibamoto, Y., Streffer, C., Fuhrmann, C. & Budach, V. (1991). Tumor radiosensitivity prediction by the cytokinesis-block micronucleus assay. Radiat Res 128: 293–300.
Shibamoto, Y., Shibata, T., Miyatake, S., Oda, Y., Manabe, T., Ohshio, G., Yagi, K., Streffer, C., Takahashi, M. & Abe, M. (1994). Assessment of the proliferative activity of human tumours using the cytokinesis-block micronucleus assay. Br J Cancer 70: 67–71.
Shibamoto, Y., Ike, O., Shibata, T., Takahashi, M., Abe, M. & Streffer, C. (1998). The cytokinesis-block micronucleus assay for the prediction of proliferative activity and radiosensitivity of human tumors. In Progress in Radio-Oncology VI, Kogelnik HD and Sedlmayer F (eds), pp. 509–515. Munduzzi Editore: Bologna, Italy
Slavotinek, A., McMillan, T. J. & Steel, C. M. (1993). A comparison of micronucleus frequency and radiation survival in lymphoblastoid cell lines. Mutagenesis 8: 569–575.
Stap, J. & Aten, J. A. (1990). Comparison of radiation sensitivity for three cell lines as measured by the cloning assay and the micro-nucleus test. Strahlenther Onkol 166: 761–763.
Villa, R., Zaffaroni, N., Gornati, D., Costa, A. & Silvestrini, R. (1994). Lack of correlation between micronucleus formation and radiosensitivity in established and primary cultures of human tumours. Br J Cancer 70: 1112–1117.
Wandl, E. O., Ono, K., Kain, R., Herbsthofer, T., Heinert, G. & Hobarth, K. (1989). Linear correlation between surviving fraction and the micronucleus frequency. Int J Radiat Biol 56: 771–775.
Weissenborn, U. & Streffer, C. (1991). Micronuclei with kinetochores in human melanoma cells and rectal carcinomas. Int J Radiat Biol 59: 373–383.
West, C. M. L. & Hendry, J. H. (1992). Intrinsic radiosensitivity as a predictor of patient response to radiotherapy. Br J Radiol 24: 146–152.
West, C. M. L., Davidson, S. E., Roberts, S. A. & Hunter, R. D. (1993). Intrinsic radiosensitivity and prediction of patient response to radiotherapy for carcinoma of the cervix. Br J Cancer 68: 819–823.
West, C. M. L., Davidson, S. E., Roberts, S. A. & Hunter, R. D. (1997). The independence of intrinsic radiosensitivity as a prognostic factor for patient response to radiotherapy of carcinoma of the cervix. Br J Cancer 76: 1184–1190.
Whitaker, S. J., Ung, Y. C. & McMillan, T. J. (1995). DNA double-strand break induction and rejoining as determinants of human tumour cell radiosensitivity. A pulsed-field gel electrophoresis study. Int J Radiat Biol 67: 7–18.
Widel, M., Dobrut, M., Maka, B., Lubecka, B. & Pluciennik, A. (1997). The radiosensitivity of human malignant melanomas evaluated by cytokinesis-block micronucleus assay. Neoplasma 44: 109–116.
Widel, M., Konopacka, M., Jedrus, S. & Owczarek, S. (1993). Evaluation of the human cervical carcinoma cells radiosensitivity by the micronucleus assay. Abstracts from Annual Meeting of ESRB, Stockholm, Sweden
Zamboglou, N., Streffer, C., Fritzmeir, C. U., Bojar, H., Karstens, J. H., Schnabel, T., Kolotas, C. & Schmitt, G. (1992). Klinische Prognose Faktoren der Radioresistenz by Kopf-Hals-Karzinomen. Dtsch Z Mund Kiefer Gesichts Chir 16: 82–85.
Zölzer, F., Alberti, W., Pelzer, T., Lamberti, G., Hulskamp, F. H. & Streffer, C. (1995). Changes in S phase fraction and micronucleus frequency as prognostic factor in radiotherapy of cervical carcinoma. Radiother Oncol 36: 128–132.
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Widel, M., Jędruś, S., Owczarek, S. et al. The increment of micronucleus frequency in cervical carcinoma during irradiation in vivo and its prognostic value for tumour radiocurability. Br J Cancer 80, 1599–1607 (1999). https://doi.org/10.1038/sj.bjc.6690569
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DOI: https://doi.org/10.1038/sj.bjc.6690569
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