Comparison Between Intracerebral Biodistribution Of [125 I] Iudr In A Rat Glioma Model And [125 I]Iudr Uptake In Spheroid Multicellular Culture: Effect Of Proliferative Heterogeneity

Document Type : Original Article




Introduction: Radioiodinated iodo deoxyuridine (IUdR) is a novel,cycle-specific agent that has potential for the treatment of residual malignant glioma after surgery. Because this thymidine analogue kills only roliferating cells. However, maligment cells which are not synthesizing DNA during exposure to the radio pharmaceutical will be spared. To determine whether tumour incroporation [125 I]IUdR could be enhanced by protracted administration we employed three different delivery methods such as single injection, polymer implant and using osmotic pump in an in vivo study in compare with an in vitro study using multicellular glioma spheroids of a range of sizes and incubation times.
Methods and Materials: We used a C6 cell line, growing in the brains of Wistar rats, as a glioma model and compared biodistribution of radiopharmaceutical in glioma cells by using autoraiogarphy method. Autoradiogarphy technique also used to discribe means of [125 I]IUdR incorporation at different times and depths within UVW multicellular glioma spheroids of a range of sizes.
Results: Twenty-four hours after administration of drug, autoradiography of brain section demonstrated nuclear uptake of the radiopharmaceutical in cells throughout tumour while normal brain cells remained free of radioactivity. The [125 I]IUdR labelling indices (%±s.e.m.) achieved were 6.2 (0.4) by single injection, 22.5 (4.1) using a sustained release polymer implant (poly lactide-co-glycolide) and 34.3 (2.0) mini-osmotic pump. The results of the spheroids study confirm that incorporation of [125 I]IUdR decreased markedly with increasing size of spheroid. The distribution of IUdR was uniform throught small spheroids (<200μm), while the concentration of IUdR occurred predominantly in the peripheral cells of larger spheroids. The IUdR uptake enhancement occurred by increasing the incubation time from 52 hours to 104 hours i.e. one or two multiples of the initial volume doubling time.
Cunclusion: The results obtained from in vitro and in vivo studies emphasize the need for a sustained delivery system as a prerequisite for effective treatment. Thses findings are also encouraging for the development of a sustained release for radiolabelled IUdR for use in the treatment of intracranial tumours, particularly in the immediate postoperative setting.