Incorporation of iododeoxyuridine in multicellular glioma spheroids: implications for DNA-targeted radiotherapy using Auger electron emitters

Abstract

Summary A promising new treatment for glioma involves Auger electron emitters such as 1251 or 1231 conjugated to deoxyuridine (lUdR). However, the presence in tumour deposits of non-proliferating cells with clonogenic potential poses a major limitation to this cycle-specific therapy. We have used multicellular tumour spheroids derived from the human glioma cell line UVW to study [1251]1UdR-targeted radiotherapy in aggregates containing cells in different proliferative states. Autoradiographic identification of labelled cells indicated that nuclear incorporation of [1251]1UdR decreased markedly with increasing size of spheroid. IUdR incorporation was maximal in the surface layer of cells and decreased with depth within spheroids. Radiopharmaceutical uptake corresponded closely to the regions of cell cycling as indicated by staining for the nuclear antigen Ki67. The uptake of drug was enhanced by increasing the duration of incubation from 52 h to 104 h. These observations suggest that significant sparing of non-cycling malignant cells would result from treatment delivered as a single injection of radiolabelled lUdR. To achieve maximal therapeutic effect, lUdR should be administered by multiple injections, by slow release from biodegradable implants or by slow-pump delivery.

Inhibition of Fatty Acid Synthase Sensitizes Prostate Cancer Cells to Radiotherapy

“…Dose enhancement ratios observed were 1.49, indicating sensitization. Furthermore, the spheroid growth delay assay used in this study provided a more reliable estimate of the response of prevascular metastases to experimental therapy than two-dimensional cell culture models (31). Using this methodology, C75 was observed to sensitize prostate cancer cells to radiation.…”

“…Thereafter, spheroids were irradiated or resuspended in serum-free culture media containing C75. After treatment, the spheroids were washed twice and those of approximately 100 lm in diameter were transferred individually into agar-coated wells of 24-well plates, as previously described (31). Individual spheroid growth was monitored twice weekly for three weeks using an inverted phasecontrast microscope connected to an image acquisition system.…”

Evaluation of the radiosensitizing potency of chemotherapeutic agents in prostate cancer cells

“…Individual spheroid growth was monitored twice per week for 3 weeks using an inverted phase-contrast microscope connected to an image acquisition system. Two perpendicular diameters, d max and d min , were measured using image analysis software (ImageJ) and the volume, V (lm 3 ), was calculated using the formula: Neshasteh-Riz et al 1997). The area under the V/V 0 versus time curve (AUC) was calculated for individual spheroids using trapezoidal approximation.…”

The Role of Copper in Disulfiram-Induced Toxicity and Radiosensitization of Cancer Cells

“…The UVW cell line was derived from a human glioblastoma (21). Cell lines were authenticated in-house using the AmpF/STR Identifiler kit (Applied BioSystems).…”