Deriving cell survival curves from the overall responses of irradiated tumours: Analysis of published data for tumour spheroids

Abstract

Summary Curves of growth delay (GD) or 'cure' after graded doses of radiation have been analysed for 16 lines of human and animal tumours grown as multicellular spheroids in vitro. Dose-survival curves were derived for those cellular units from which spheroids regrow after unsuccessful irradiation (spheroidregenerating cellular units, SRU). For 10 sets of data from 6 spheroid lines, the Do's and extrapolation numbers of the SRU derived by GD could be compared with the response of the clonogenic cells of the spheroids. For Do, a good correlation (r=0.910) was found between the two; this was true also for Do derived from curves of spheroid 'cure' (7 sets of data from 6 spheroid lines) and clonogenic cells (r=0.986). Using GD, the correlation of extrapolation numbers was less good (r=0.682), the values for SRU commonly being higher than those for clonogenic cells. This may reflect features of the growth curves of spheroids after the lower range of doses of radiation. For human and animal tumour spheroids of 250 tm or less, derived Do ranged from 0.5 to 2.5Gy. For spheroids of 350pm or more, derived Do for animal tumour lines ranged from 3.4 to 4.2Gy, for human lines from 1.5 to 2.1 Gy.Several attempts have been made to infer the radiobiological characteristics of the cells (tumour-regenerating cellular units; TRU) that determine whether in situ tumours regrow or not after irradiation. Deductions have been made from the overall responses of populations of tumours, i.e. from the shapes of dose-response curves for delay in tumour regrowth (e.g. Thomlinson and Craddock, 1967;Denekamp and Harris, 1975) or for tumour local control (e.g. Suit, 1966;Moore et al., 1983). There exist a few experimental studies on macroscopic tumours in which good agreement has been found between the Do's for clonogenic cells and values for TRU derived from local control, e.g. for the RI rhabdomyosarcoma made artificially hypoxic by clamping (Rheinhold & de Bree, 1968). However, in most cases the derived Do for TRU has been 2 to 3 times higher than that for clonogenic cells of tumours treated either 'in air' (Moore et al., 1983) or clamped (from an analysis of data quoted by Moulder & Rockwell, 1984). Although, in principle, an equation between the overall response of a macroscopic tumour and the response of its clonogenic cells may be realisable, heterogeneity in number of TRU, degree of oxygenation, repair capabilities, and possibly in some cases radiation dose received, will usually result in derived values of Do that are systematically higher than those for clonogenic cells. Additionally, as noted most recently by Wheldon et al. (1985), the outcome of these calculations for tumours in situ may be complicated by factors such as the tumour bed effect, possible immunological responses, and the maximum size that tumours can be allowed to attain in experimental animals. It was suggested that tumour spheroids growing in vitro might be particularly suitable experimental models in this context, for studying the primary features of cell and tumour...

<I>Effects of X-irradiation Alone and in Combination with ACNU on Human Glioblastoma Cells in Vitro</I>

“…Thus, the data of animal tumors described above may be possibly due to large variations.5) The study of spheroids is advantageous in such analysis. 2,8,9,13,15,16,19,20,25,27) In our study, with small spheroids the values of D0 and N0 ,E , n derived from both the cell survival and spheroid control rate curves were almost the same, confirming the reliabili ty of this experimental system. Similar results have been obtained in studies of small spheroids of human melanoma cells and V-79 cells.…”

131I-meta-iodobenzylguanidine therapy in neuroblastoma spheroids of different sizes

“…The endpoints of regrowth delay and 'cure' were chosen as a good correlation has been shown between tumour spheroid radiosensitivity estimates derived from regrowth delay, cure and clonogenic assays (Pourreau-Schneider & Malaise, 1981;West et al, 1984;Moore et al, 1987).…”