ToxSci Advance Access published online on July 25, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg188
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 Institute of Microbiology, Milan, Italy
* To whom correspondence should be addressed. E-mail: augusto.pessina{at}unimi.it.
In a previous study of prevalidation, a Standard Operating Procedure (SOP) for two independent in vitro tests (human and mouse) has been developed, to evaluate the potential hematotoxicity of xenobiotics from their direct, adverse effects on CFU-GM. A predictive model to calculate the human Maximum Tolerated Dose (MTD) was set up, by adjusting mouse-derived MTD for the differential inter-species sensitivity. In this report, we describe an international blind trial designed to apply this model to the clinical neutropenia, by testing 20 drugs including 14 antineoplastics (Cytosar-U, 5-Fluorouracil, Myleran, Thioguanine, Fludarabine, Bleomycin, Methotrexate, Gemcitabine, Carmustine, Etoposide, Teniposide, Cytoxan, Taxol, Adriamycin); 2 antivirals (Retrovir, Zovirax,); 3 drugs for other therapeutic indications (Cyclosporin, Thorazine, Indocin) and 1 pesticide (Lindane). The results confirmed that the SOP developed generates reproducible IC90 values both with human and murine GM-CFU. For 10 drugs (Adriamycin, Bleomycin, Etoposide, Fludarabine, 5-Fluorouracil, Myleran, Taxol, Teniposide, Thioguanine and Thorazine) IC90 values were found within the range of the actual drug doses tested (defined as actual IC90). For other 10 drugs (Carmustine, Cyclosporin, Cytosar-U, Cytoxan, Gemcitabine, Indocin, Lindane, Methotrexate, Retrovir and Zovirax) extrapolation on the regression curve out of the range of the actual doses tested was required to derive IC90 values (extrapolated IC90). The model correctly predicted the human MTD for 10 drugs out of 10 that had "actual IC90 values" and 7 drugs out of 10 for those having only an extrapolated IC90. Two of the incorrect predictions (Gemcitabine and Zovirax) were within 6-fold of the correct MTD, instead of the 4-fold range required by the model whereas prediction with Cytosar-U was We concluded that our model correctly predicted the human MTD for 20 drugs out of 23, since other three drugs (Topotecan, PZA and Flavopiridol) were tested in the prevalidation study. The high percentage of predicitivity (87%), as well as the reproducibility of the SOP testing, confirm that the model can be considered scientifically validated in this study, suggesting promising applications to other areas of research in developing validated hematotoxicological in vitro methods.
© 2003 Society of Toxicology
In Vitro Toxicology and Alternative Testing
Application of the GM-CFU Assay to Predict Acute Drug-Induced Neutropenia: An International Blind Trial to Validate a Prediction Model for the Maximum Tolerated Dose (MTD) of Myelosuppressive Xenobiotics
2 CIEMAT, Madrid, Spain
3 BIBRA International, Carshalton, UK
4 ECVAM, Institute for Health and Consumer Protection, Joint Research Centre, European Commission, Ispra, Italy
5 Wayne State University, Detroit, USA
6 ESMISAB, Plouzanè, France
7 VITO, Mol, Belgium
Abstract 
10-fold in error. A possible explanation of the failure in the prediction of these 3 drugs, which are pyrimidine analogs, is discussed.
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