The response to cytotoxic drugs of EMT6 cells treated either as intact or disaggregated spheroids

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Abstract
We have compared the response to a number of cytotoxic drugs of cells treated either within intact multicellular spheroids or as isolated cells following spheroid disaggregation. The cells used were of the EMT6/Ca/VJAC mouse tumour line and spheroids were treated or disaggregated at a mean diameter of 250 micron. The response of cell to nitrogen mustard (HN2) or CCNU was similar under the two exposure conditions and we conclude that factors related to spheroid structure (i.e. drug penetrability, intercellular contact effect and microenvironment within the spheroid) do not influence the initial response to these agents. Recovery of potentially lethal damage occurring over 24 h, however, greatly modifies the level of cell killing in intact spheroids. EMT6 cells were found to be extremely resistant to vincristine under all exposure conditions. For adriamycin (ADM), cells were always initially more sensitive when exposed to the drug in suspension rather than in intact spheroids. When ADM exposure was prolonged beyond 1 h, however, delaying spheroid disaggregation for 24 h led to increased cell kill and reduced differential between the two conditions of exposure. The data suggest that both drug penetration problems and other factors related to spheroid structure are involved in determining the response of cells in small spheroids to ADM.