ATLA::Alternatives to Laboratory Animals

Volume 30, Supplement 2

In vitro tests for haematotoxicity- prediction of drug-induced myelosuppression by the CFU-GM assay

ATLA 30, Supplement 2, 75-79, 2002

Augusto Pessina,¹ Beatriz Albella,² Maria Bayo,¹ Juan Bueren,² Paul Brantom,³ Silvia Casati,⁴ Cristina Croera,¹ Ralph Parchment,⁵ Dominique Parent-Massin,⁶ Greet Schoeters,⁷ Yann Sibiri,⁶ Rosette Van Den Heuvel⁷ and Laura Gribaldo⁴

¹Institute of Microbiology, University of Milan, via Pascal 36, 20133 Milan, Italy; ²CIEMAT, Av. Complutense 2Z 28040 Madrid, Spain; ³BIBRA International, Carshalton, Surrey SM5 4DS, UK; ⁴ECVAM, Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra 21020 (VA), Italy; ⁵Wayne State University, Detroit, MI 48202 USA; ⁶ESMISAB, Technopôle, Best-froise 29280, Plouzané, France; ⁷VIT0, Boezetang 200, 2400 Mol, Belgium

SUMMARY

In a prevalidation study, a Standard Operating Procedure (SOP) for human and mouse in vitro tests was developed, for evaluating the potential haematotoxicity of xenobiotics in terms of their direct, adverse effects on the myeloid colony-forming unit (CFU-GM). Based on the adjustment of the mouse-derived maximum tolerated dose (MTD), a prediction model was set up to calculate the human MTD, and an international blind trial was designed to apply this model to the clinical neutropenia of 23 drugs including 17 antineoplastics. The model correctly predicted the human MTD for 20 drugs out of the 23 (87%). This high percentage of predictivity, and the reproducibility of the SOP testing, confirmed the scientific validation of this model, and suggested promising applications for developing and validating other in vitro methods for use in haematotoxicology.

Keywords: acute neutropenia, CFU-GM assay, maximum tolerated dose, myelotoxicity