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Title: Radiolabelled iododeoxyuridine for experimental targeted radiotherapy of glioma
Author: Neshasteh-Riz, Ali
ISNI:       0000 0001 3441 5333
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1997
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Gliomas are the most common primary tumours arising in the human brain. The most malignant glioma, the glioblastoma, represents 5000 new cases per year in the United States. Despite surgery, chemotherapy, and radiotherapy, glioblastomas are almost always fatal, with a median survival of less than a year and a 5-year survival rate of 5.5% or less. After treatment, recurrent disease often occurs locally; systemic metastases are rare. Neurologic dysfunction and death are from local growth. No therapeutic modality has substantially changed the outcome of patients with glioblastoma. Therefore, we have explored a novel form of treatment: targeted radiotherapy using radioiododeoxyuridine, a thymidine analogue that is intended to destroy glioma cells yet spare normal brain tissue. Radiolabelled IUdR is an appropriate targeting vehicle for the delivery of radiation to proliferating tumour target tissue. This study included an investigation of the most suitable radioisotopes to conjugate to IUdR. Heterogeneous proliferative activity of glioma cells (ie non-cycling cells) is one of the main barriers to the therapeutic potential of radiolabelled IUdR. Therefore, an important part of this work was obtaining appropriate models for the study of human gliomas in vitro. We thus employed spheroids derived from UVW, SB 18 and U251 glioma cell lines, as well as cells in exponential monolayer growth and plateau phase for this evaluation. Multicellular spheroids grown from established cell lines have been shown to have growth kinetics similar to in vivo tumours. As with the clinical situation, in the spheroid model there is an increase in the number of resting cells as the size of the mass enlarges and also there are nonproliferating cells and necrosis in the more central hypoxic area. The UVW cell line was chosen because of its capability to grow as very large and regularly shaped spheroids. The karyotype anlaysis of UVW cell line revealed a highly aneuploid cell line. This cell line was also very radioresistant in both monolayer and spheroid cultures as determined by external beam radiation experiments. The survival fraction values obtained at 2 Gy (SF2) were 0.55 for exponential monolayer cells and 0.83-0.93 for spheroids gained from clonogenic assay and growth delay experiments respectively. These values place this cell line at the radioresistant part of the spectrum of human cell line radiosensitivity. We assessed the effect of proliferative heterogeneity on the uptake of non-radiolabelled IUdR by studying different sizes of UVW human glioma spheroids and monolayer cell cultures in exponential and plateau phases, in conjunction with flow cytometry. The results of the study confirm that there is an inverse relationship between the proportion of cycling cells and spheroid diameter. In monolayer cultures more than 95% of exponentially growing cells and 62% of plateau phase cells were labelled with IUdR after one doubling time. However, the labelling index in the small spheroids (100-200mum) was approximately 76% and 28% for large spheroids (700-1000mum) after one volume doubling time incubation (52 hours). The proportion of cells that incorporate IUdR is small and large sizes of spheroids increased with increasing the period of incubation with IUdR from one to four volume doubling times. The effect of spheroid size and incubation time on labelling index was also evaluated in conjunction with autoradiography and Ki67 immunostaining. In these experiments nuclear incorporation of [125I]IUdR decreased markedly with increasing size of spheroid. The distribution of IUdR was uniform throughout small spheroids (< 200mum), while the concentration of IUdR occured predominantly in the peripheral cells of larger spheroids. Radiopharmaceutical uptake corresponded closely to the regions of cell cycling as indicated by staining for the nuclear antigen Ki67. The IUdR uptake enhancement occurred by increasing the incubation time from 52 hours to 104 hours. It was concluded that a single injection of radioiodinated IUdR would be insufficient to sterillise all of the malignant cells. Therefore, to achieve maximal therapeutic benefit IUdR should be administered either by multiple injections or by slow release from polymers or slow-pump delivery.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Brain tumours