In vitro bone marrow granulocyte-macrophage progenitor cultures in the assessment of hematotoxic potential of the new drugs

In pharmaceutical research, in vitro toxicity tests, for assessing the pote ntial toxicity of new chemical entities are necessary in the early stages o f the developmental process, when no information is available about the met abolism or even the target organ toxicity of the compounds to be tested. In vitro specific organ toxicity tests, such as the granulocyte-macrophage co lony-forming unit (CFU-GM) clonogenic assay, are useful tools for predictin g the adverse effects of new compounds on the blood-forming system, provide d that some reference points are available, e.g., toxicological information about compounds belonging to the same chemical class and structure-activit y relationship data. Furthermore, when no information is available about me tabolism, the in vitro system should cover as many possibilities as possibl e, to avoid false positive or false negative results. In fact, while many c ompounds are metabolized to a variety of inactive chemical species, some un dergo bioactivation to form more active metabolites. The addition of a meta bolic activation system to the CFU-GM assay enables assessment of direct an d metabolism-mediated toxicity. The regulatory agencies and industry value the concept of assays performed with and without metabolic activation, sinc e they often have to take decisions about compounds with unknown mechanisms of action. CFU-GM assay, designed in this way, is an example of such a mec hanism-naive assay. It has been suggested that, for new compounds, metabolites should be genera ted and tested both in the presence and in the absence of the parent compou nd itself, to identify the possible contribution of metabolites to the hema totoxicity observed, and to determine whether there is any synergistic or a ntagonistic effect between metabolites and the parent compound that might a ffect hematotoxicity in vivo. Various approaches can be used to obtain such information.