A new method to evaluate in vitro myelotoxicity of antitumour agents in the first steps of drug development

Research focused on the development of new anticancer agents has been based mainly on the assessment of the antitumour activity. This yields a large n umber of newly developed drugs endowed with good antitumour properties, but heavy side-effects on myelopoiesis. In this work, we validate a new method potentially useful to assess myelotoxic effect of newly developed agents. The proposed technique uses peripheral blood CD34+ cells as source of haema topoietic progenitors. These cells are grown in liquid culture in the prese nce of cytokines able to induce differentiation versus the three main linea ges. Doxorubicin, carboplatin and topotecan served as reference drugs to in vestigate the accuracy of the technique. The three drugs mimick the effects reported in vivo. Doxorubicin and carboplatin produce a specific effect to ward erythropoietic and thrombopoietic lineages, respectively, and topoteca n a three-lineage toxicity. An advantage of the technique is the possibilit y to further investigate myelotoxicity. Here, we assessed differentiation m arkers in CD34+ cells to evaluate if the three drug treatments can affect t he process of differentiation. Data show that the drug treatments were unab le to modulate the expression of the selected differentiation markers in th e surviving population. We propose this method as an innovative tool to sco re the myelotoxic effect of compounds in the first steps of drug developmen t to further develop those compounds with the best ratio between activity a nd myelotoxic effects. Moreover, the fact that the method is performed in l iquid phase allows its optimisation in a conventional "high throughput syst em".