Abstract
Tumour angiogenesis is essential for progression of solid tumours and constitutes an interesting target for therapy. However, impaired tumour blood supply may also be an important obstacle for treatment by radiotherapy and chemotherapy. Estramustine has been shown to increase tumour blood flow and potentiate the effect of radiotherapy in experimental glioma. This study investigated the effects of fractionated radiotherapy and estramustine on angiogenesis in malignant glioma. The intracerebral BT4C rat glioma model was used and the animals were given whole brain radiotherapy 4 Gy × 5 days alone or in combination with estramustine 20 mg kg-1 i.p. daily. Tumour microvascular density (MVD) was assessed by manual and computerized morphometrical analysis. Expression of vascular endothelial growth factor (VEGF) was studied by in situ hybridization. Radiotherapy decreased MVD to 157 vessels per mm2 compared to 217 vessels per mm2 in controls. Estramustine counteracted this anti-angiogenic effect and potentiated the anti-tumoural effect of radiotherapy. In addition, vessel size increased after estramustine treatment. Five days after completion of radiotherapy the expression of VEGF was increased in the centre of the tumours. In conclusion, fractionated radiotherapy decreases microvascular density in experimental malignant glioma. This effect was abolished by estramustine. The anti-vascular effect of irradiation is important to recognize when combining radiotherapy with cytotoxic drugs.
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References
Baker, D. G. & Krochak, R. J. (1989) The response of the microvascular system to radiation: a review. Cancer Invest 7: 287–294.
Banerjee, S. K., Sarkar, D. K., Weston, A. P., De, A. & Campbell, D. R. (1997) Overexpression of vascular endothelial growth factor and its receptor during the development of estrogen-induced rat pituitary tumors may mediate estrogen-initiated tumor angiogenesis. Carcinogenesis 18: 1155–1161.
Bergenheim, A. T., Gunnarsson, P. O., Edman, K., von Schoultz, E., Hariz, M. I. & Henriksson, R. (1993) Uptake and retention of estramustine and the presence of estramustine binding protein in malignant brain tumours in humans. Br J Cancer 67: 358–361.
Bergenheim, A. T., Elfversson, J., Gunnarsson, P-O, Edman, K., Hartman, M. & Henriksson, R. (1994a) Cytotoxic effect and uptake of estramustine in a rat glioma model. Int J Oncol 5: 293–299.
Bergenheim, A. T., Björk, P., Bergh, J., von Schoultz, E., Svedberg, H. & Henriksson, R. (1994b) Estramustine-binding protein and specific binding of the anti-mitotic compound estramustine in astrocytoma. Cancer Res 54: 4974–4979.
Bergenheim, A. T., Zackrisson, B., Elfverson, J., Roos, G. & Henriksson, R. (1995) Radiosensitizing effect of estramustine in malignant glioma in vitro and in vivo. J Neuro-Oncol 23: 191–200.
Bergenheim, A. T., Henriksson, R., Piepmeier, J. M. & Yoshida, D. (1996) Estramustine in malignant glioma. J Neuro Oncol 30: 81–89.
Cullinan Bove, K. & Koss, R. D. (1993) Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology 133: 829–837.
Denekamp, J. (1991) The current status of targeting tumour vasculature as a means of cancer therapy: an overview. Int J Radiat Biol 60: 401–408.
Denekamp, J. & Hobson, B. (1982) Endothelial-cell proliferation in experimental tumours. Br J Cancer 46: 711–720.
Dewhirst, M. W., Oliver, R., Tso, C. Y., Gustafson, C., Secomb, T. & Gross, J. F. (1990) Heterogeneity in tumor microvascular response to radiation. Int J Radiat Oncol Biol Phys 18: 559–568.
Ferrara, N. (1996) Vascular endothelial growth factor. Eur J Cancer 32a: 2413–2422.
Folkman, J. (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186.
Folkman, J. (1990) What is the evidence that tumors are angiogenesis dependent? (editorial). J Natl Cancer Inst 82: 4–6.
Gasparini, G. & Harris, A. L. (1995) Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool. J Clin Oncol 13: 765–782.
Gray, L. H. (1961) Radiobiologic basis of oxygen as a modifying factor in radiation therapy. Am J Roentgenol 85: 803
Hall, E. J. (1994). Radiobiology for the Radiologist. Lippincott: Philadelphia
Hatjikondi, O., Ravazoula, P., Kardamakis, D., Dimopoulos, J. & Papaioannou, S. (1996) In vivo experimental evidence that the nitric oxide pathway is involved in the X-ray-induced antiangiogenicity. Br J Cancer 74: 1916–1923.
Henderson, S. D., Kimler, B. F. & Morantz, R. A. (1981) Radiation therapy of 9L rat brain tumors. Inl J Radiat Oncol Biol Phys 7: 497–502.
Hilmas, D. E. & Gillette, E. L. (1975) Tumor microvasculature following fractionated x irradiation. Radiology 116: 165–169.
Jain, R. K. (1987) Transport of molecules across tumor vasculature. Cancer Metab Rev 6: 559–593.
Johansson, M., Bergenheim, A. T., Henriksson, R., Koskinen, L. O., Vallbo, C. & Widmark, A. (1997) Tumor blood flow and the cytotoxic effects of estramustine and its constituents in a rat glioma model. Neurosurgery 41: 237–243; discussion 243–244.
Johansson, M., Bergenheim, A. T., D’Argy, R., Edman, K., Gunnarsson, P., Widmark, A. & Henriksson, R. (1998) Distribution of estramustine in the BT4C rat glioma model. Cancer Chemother Pharmacol 41: 317–325.
Kelly, P. J., Daumas-Dauport, C., Kispert, D. B., Kall, B. A., Scheithauer, B. W. & Illig, J. J. (1987) Imaging based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg 66: 865–874.
Leon, S. P., Folkerth, R. D. & Black, P. M. (1996) Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 77: 362–372.
Lindgren, M., Johansson, M., Sandstrom, J., Jonsson, Y., Bergenheim, A. T. & Henriksson, R. (1997) VEGF and tPA co-expressed in malignant glioma. Acta Oncol 36: 615–618.
Littbrand, B. & Révész, L. (1969) The effect of oxygen on cellular survival and recovery after radiation. Br J Radiol 42: 914–924.
Morales, D. E., McGowan, K. A., Grant, D. S., Maheshwari, S., Bhartiya, D., Cid, M. C., Kleinman, H. K. & Schnaper, H. W. (1995) Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 91: 755–763.
Nakamura, J., Savinov, A., Lu, Q. & Brodie, A. (1996) Estrogen regulates vascular endothelial growth/permeability factor expression in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. Endocrinology 137: 5589–5596.
Plate, K. H., Breier, G., Weich, H. A. & Risau, W. (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359: 845–848.
Plate, K. H., Breier, G., Millauer, B., Ullrich, A. & Risau, W. (1993) Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res 53: 5822
Prionas, S. D., Kowalski, J., Fajardo, L. F., Kaplan, I., Kwan, H. H. & Allison, A. C. (1990) Effects of X irradiation on angiogenesis. Radiat Res 124: 43–49.
Rubin, P. & Casarett, G. (1966) Microcirculation of tumors. II. The supervascularized state of irradiated regressing tumors. Clin Radiol 17: 346–355.
Seiler, R. W., Zimmermann, A., Bleher, E. A. & Markwalder, H. (1979) Preoperative radiotherapy and chemotherapy in hypervascular, high-grade supratentorial astrocytomas. Surg Neurol 12: 131–133.
Shweiki, D., Itin, A., Soffer, D. & Keshet, E. (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359: 843–845.
Solesvik, O. V., Rofstad, E. K. & Brustad, T. (1984) Vascular changes in a human malignant melanoma xenograft following single-dose irradiation. Radiat Res 98: 115–128.
Song, C. W., Sung, J. H., Clement, J. J. & Levitt, S. H. (1974) Vascular changes in neuroblastoma of mice following x-irradiation. Cancer Res 34: 2344–2350.
von Schoultz, E., Lundblad, D., Bergh, J., Grankvist, K. & Henriksson, R. (1988) Estramustine binding protein and anti-proliferative effect of estramustine in human glioma cell lines. Br J Cancer 58: 326–329.
Weidner, N. (1993) Tumor angiogenesis: review of current applications in tumor prognostication. Semin Diagn Pathol 10: 302–313.
Yoshida, D., Piepmeier, J. & Weinstein, M. (1994) Estramustine sensitizes human glioblastoma cells to irradiation. Cancer Res 54: 1415–1417.
Zywietz, F. (1990) Vascular and cellular damage in a murine tumour during fractionated treatment with radiation and hyperthermia. Strahlenther Onkol 166: 493–501.
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Johansson, M., Bergenheim, A., Widmark, A. et al. Effects of radiotherapy and estramustine on the microvasculature in malignant glioma. Br J Cancer 80, 142–148 (1999). https://doi.org/10.1038/sj.bjc.6690333
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DOI: https://doi.org/10.1038/sj.bjc.6690333
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