Theoretical and practical considerations in screening strategies for differentiation agents

Abstract

Abstract This paper reviews strategies for identification of new compounds with differentiation inducing activity. The primary objective is to discriminate ‘lead’ compounds with novel mechanisms of action. Complementary to this is the need to generate a taxonomy of known compounds, identifying those with similar mechanisms, preferably in a way that provides clues as to the nature of those mechanisms. Experimental data suggest that the methods to do this are already to hand and that some existing search strategies are readily adapted to these objectives. The principal property required of the screen is that distinct mechanisms of induction produce different outcomes. Response patterns can thus be used to group drugs with similar mechanisms and hence identify novel activities. To be successful, such patterns have to be relatively insensitive to potency (so that agents with the same mechanism but different potency are classed together). Two strategies to achieve mechanism-sensitive response patterns are outlined, one based on the varied response capacities of multiple target cell types and another exploiting drug interaction patterns. With the former, the principle exploited is that the differences in the panel cells' capacities to respond depend on the components and assembly of their signal transduction and effector mechanisms for differentiation. With the latter, it is the varied and complex ways in which the components of the intracellular mechanism are assembled which provides distinctive interaction patterns, depending upon which components are the molecular targets of a particular pair of drugs. Pattern generation, analysis and optimisation of efficacy and cost/benefit are also discussed. Differentiation end-points are difficult to assess and cell number/mass may be more appropriate to high throughput designs. The problems of discriminating growth arrest due to differentiation, from other antiproliferative or simply cytotoxic effects are therefore considered and suggestions made for feasibility studies of these approaches.