Intercellular variations in the level of antigen expression and in cellular and nuclear radii were taken into account in a model used to estimate cell survival for an in vitro experiment with antibodies containing alpha-particle emitters that target the cell surface. Using measured variations in these characteristics for cells of two human cancer cell lines, the model gave results for cell survival and the fundamental parameter of radiation sensitivity, z(0), that differ substantially from those obtained using only mean values. The cell survival may be underestimated by a factor of 100 if only mean values of these cellular parameters are used, and calculated values of z(0) may be overestimated by a factor of 2. Most of this effect stems from the variation in antigen expression. The magnitudes of the differences were found to be a function of the fractions of mean specific energy delivered by surrounding activity and by activity bound to the cells.

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Intratumour heterogeneity in the uptake of blood-borne technetium-labelled human serum albumin ( 99m Tc-HSA) was studied in human melanoma xenografts in an attempt to identify transport barriers leading to inadequate and heterogeneous uptake of macromolecular therapeutic agents in tumours. The Bioscope imaging system, which can detect the distribution of 99m Tc in 10-mmthick tissue sections with a spatial resolution of just above 50 mm, was used to image the 99m Tc-HSA uptake. Xenografted tumours of four human melanoma cell lines were included in the study. Significant intratumour heterogeneity in the uptake of 99m Tc-HSA was detected. The heterogeneity had two distinctly different components, one random and one radial component. The uptake was lowest in the centre of the tumours and increased towards the tumour periphery. This radial heterogeneity was superimposed by a random heterogeneity, that is, spots with high uptake colocalised with spots with high vascular density and regions without significant uptake colocalised with necrotic regions. The magnitude of the heterogeneity did not change significantly with time after the administration of 99m Tc-HSA. The tumours showed a random and a radial heterogeneity in blood perfusion similar to that in the uptake of 99m Tc-HSA. The observations reported here suggest that the intratumour heterogeneity in the distribution of 99m Tc-HSA was initiated primarily because of heterogeneity in the supply of 99m Tc-HSA through the microvasculature, and that the presence of severe transport barriers in the tumour interstitium prevented significant equalisation of the initial heterogeneity with time. Consequently, strategies for improving the delivery of macromolecular therapeutic agents to tumours should focus on increasing the tumour blood perfusion to increase the total uptake and improving the diffusion conditions in the tumour interstitium to diminish the heterogeneity in the uptake.

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