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

Abstract：

:In pharmaceutical research, in vitro toxicity tests, for assessing the potential toxicity of new chemical entities are necessary in the early stages of the developmental process, when no information is available about the metabolism or even the target organ toxicity of the compounds to be tested. In vitro specific organ toxicity tests, such as the granulocyte-macrophage colony-forming unit (CFU-GM) clonogenic assay, are useful tools for predicting the adverse effects of new compounds on the blood-forming system, provided that some reference points are available, e.g., toxicological information about compounds belonging to the same chemical class and structure-activity relationship data. Furthermore, when no information is available about metabolism, the in vitro system should cover as many possibilities as possible, to avoid false positive or false negative results. In fact, while many compounds are metabolized to a variety of inactive chemical species, some undergo bioactivation to form more active metabolites. The addition of a metabolic activation system to the CFU-GM assay enables assessment of direct and metabolism-mediated toxicity. The regulatory agencies and industry value the concept of assays performed with and without metabolic activation, since 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 mechanism-naive assay. It has been suggested that, for new compounds, metabolites should be generated and tested both in the presence and in the absence of the parent compound itself, to identify the possible contribution of metabolites to the hematotoxicity observed, and to determine whether there is any synergistic or antagonistic effect between metabolites and the parent compound that might affect hematotoxicity in vivo. Various approaches can be used to obtain such information.

journal_name

Cell Biol Toxicol

journal_title

Cell biology and toxicology

authors

Negro GD,Bonato M,Gribaldo L

doi

10.1023/a:1010958121396

subject

Has Abstract

pub_date

2001-01-01 00:00:00

pages

95-105

issue

eissn

0742-2091

issn

1573-6822

journal_volume

pub_type

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