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 number 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 haematopoietic progenitors. These cells are grown in liquid culture in the presence of cytokines able to induce differentiation versus the three main lineages. Doxorubicin, carboplatin and topotecan served as reference drugs to investigate the accuracy of the technique. The three drugs mimick the effects reported in vivo. Doxorubicin and carboplatin produce a specific effect toward erythropoietic and thrombopoietic lineages, respectively, and topotecan a three-lineage toxicity. An advantage of the technique is the possibility to further investigate myelotoxicity. Here, we assessed differentiation markers in CD34+ cells to evaluate if the three drug treatments can affect the process of differentiation. Data show that the drug treatments were unable to modulate the expression of the selected differentiation markers in the surviving population. We propose this method as an innovative tool to score the myelotoxic effect of compounds in the first steps of drug development to further develop those compounds with the best ratio between activity and myelotoxic effects. Moreover, the fact that the method is performed in liquid phase allows its optimisation in a conventional "high throughput system".
Ferlini
C
C
Department of Obstetrics and Gynaecology, Catholic University Sacro Cuore, Rome, Italy. ferlini@iol.it
Distefano
M
M
Pierelli
L
L
Bonanno
G
G
Fattorossi
A
A
Battaglia
A
A
Mancuso
S
S
Scambia
G
G
D018952:Antigens, CD34 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology; D004920:Erythropoiesis / Q000187:drug effects; D005434:Flow Cytometry / Q000379:methods; D006021:Glycophorins / Q000187:drug effects / Q000378:metabolism; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007937:Leukapheresis / Q000379:methods; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000187:drug effects*; D015203:Reproducibility of Results; D013926:Thrombopoietin / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D019772:Topotecan / Q000494:pharmacology
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D006021:Glycophorins; D019772:Topotecan; D004317:Doxorubicin; D013926:Thrombopoietin; D016190:Carboplatin