Regional heterogeneity and pharmacodynamics in human solid tumor histoculture

Purpose: Human solid tumor histocultures represent a clinically relevant ex perimental system for pharmacodynamic study. The evaluation of the drug-ind uced antiproliferative effect in histocultures is usually performed by manu al microscopic scoring of individual cells. This procedure, because of its labor intensive nature, is performed on a single microscopic field, i.e. th e field with the highest proliferative activity. Because regional heterogen eity in a solid tumor may result in different drug sensitivities in differe nt parts of a tumor, there is the question as to whether the pharmacodynami c data determined in the most proliferative field is representative of thos e in the whole tumor. This question was addressed in the present study. Met hods: A recently developed automated image analysis method was used to meas ure the labeling index of tumor cells. The drug-induced inhibition of DNA p recursor incorporation into nuclei of cells in the region with the highest proliferative activity was compared to the inhibition in cells in the entir e histoculture. This study was performed in human bladder tumor histocultur es treated with several drugs (doxorubicin, mitomycin C, paclitaxel and 5-f luorouridine). A total of 724 pairs of data obtained from untreated and dru g-treated histocultures (each data point representing the average of 1 to 6 tumor histocultures) were analyzed. Results: The absolute value of the lab eling index in the most proliferative region (LIone) was significantly high er than the absolute value of the labeling index in the whole tumor (LIall) , in both untreated and drug treated samples (mean difference of 18%, range 1-27%). However, when the absolute LI values in drug-treated samples were normalized to the values in untreated controls and expressed as a percentag e of control, and used to construct the concentration-response curves, the two curves obtained using LIone and LIall yielded comparable pharmacodynami c parameters, i.e. curve shape parameters and drug concentrations that prod uce 30, 50, and 70% inhibition. Conclusion. These results indicate comparab le pharmacodynamics in the most proliferative region and the whole tumor, a nd confirm the validity of using the most proliferative field for evaluatin g chemosensitivity in solid tumor histocultures.