Differential cytotoxicity of [123I]IUdR, [125I]IUdR and [131I]IUdR to human glioma cells in monolayer or spheroid culture: effect of proliferative heterogeneity and radiation cross-fire

Abstract

Radioiodinated iododeoxyuridine (IUdR) is a novel, cycle-specific agent that has potential for the treatment of residual malignant glioma after surgery. As only cells in S-phase incorporate IUdR into DNA, a major limitation to this therapy is likely to be proliferative heterogeneity of the tumour cell population. Using a clonogenic end point, we have compared the toxicities of three radioiodoanalogues of IUdR--[123I]IUdR, [125I]IUdR and [131I]IUdR--to the human glioma cell line UVW, cultured as monolayers in the exponential and the plateau phase of growth and as multicellular spheroids. Monolayers treated in the exponential growth phase were most efficiently sterilized by [125I]IUdR (concentration resulting in 37% survival (C37) = 2.36 kBq ml(-1)), while [123I]IUdR and [131I]IUdR were less effective eradicators of clonogens (C37 = 9.75 and 18.9 kBq ml(-1) respectively). Plateau-phase monolayer cultures were marginally more susceptible to treatment with [123I]IUdR and [125I]IUdR (40% clonogenic survival) than [131I]IUdR (60% clonogenic survival). In cells derived from glioma spheroids, both [125I]IUdR and [123I]IUdR were again more effective than [131I]IUdR at concentrations up to and including 20 kBq ml(-1). However, the survival curve for [131I]IUdR crossed the curves for the other agents, resulting in lower survival for [131I]IUdR than [123I]IUdR and [125I]IUdR at concentrations of 40 kBq ml(-1) and higher, the clonogenic survival values at 100 kBq ml(-1) were 13%, 45% and 28% respectively. It was concluded that IUdR incorporating the Auger electron emitters 123I and 125I killed only cells that were in S-phase during the period of incubation with the radiopharmaceutical, whereas the superior toxicity to clonogenic cells in spheroids of [131I]IUdR at higher concentration was due to cross-fire beta-irradiation. These findings suggest that [131I]IUdR or combinations of [131I]IUdR and [123I]IUdR or [125I]IUdR may be more effective than Auger electron emitters alone for the treatment of residual glioma, if proliferative heterogeneity exists.

Transfectant mosaic spheroids: a new model for evaluation of tumour cell killing in targeted radiotherapy and experimental gene therapy

“…As expected, the cell kill increased with increasing proportion of NAT‐expressing cells. As was seen in previous studies, cytotoxicity was more pronounced in the three‐dimensional spheroids, probably as a result mainly of radiation cross‐fire which is more efficacious in three‐dimensions6, 7, 19, 20. In the present study, the response of TMS to [ 131 I]MIBG treatment was evaluated by clonogenic assay and spheroid growth delay.…”

Applications of Gene Transfer to Targeted Radiotherapy

“…This type of collateral cell kill has previously been demonstrated using the tumor spheroid culture system. Cunningham et al [70] and Neshasteh-Riz et al [71] have shown that the effectiveness of cell kill by [ 131 I]-labelled compounds is significantly underestimated using monolayer cultures of target tumour cells whereas the impressive collateral damage inflicted by this means is amply demonstrated using threedimensional cellular aggregates.…”

“…(2)). The increased effectiveness of radionuclide treatment of cellular aggregates is due to the enhanced efficiency of absorption of decay energy in three dimensional cultures [49,70,71]. If the administered radioisotope of iodine was 131 I (half-life = 8 days), the short residence time in NIS-expressing cells would diminish the radiation dose to tumours.…”

Targeting Radiotherapy to Cancer by Gene Transfer

“…The increased effectiveness of radionuclide treatment of cellular aggregates is due to the enhanced efficiency of absorption of decay energy in three-dimensional cultures [34, 44]. This cross fire irradiation phenomenon (Figure 3) is an especially attractive feature of gene therapy schemes involving cellular concentration of radionuclides since gene transfer is notoriously inefficient, necessitating a mechanism which achieves bystander cell kill.…”