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This report describes an international pre-validation study conducted to optimise the Standard Operating Procedure (SOP) for detecting myelosuppressive agents by CFU-GM assay and to study a model for predicting (by means of this in vitro hematopoietic assay) the acute xenobiotic exposure levels that cause maximum tolerated decreases in absolute neutrophil counts (ANC). In the first phase of the study (Protocol Refinement), two SOPs were assessed, by using two cell culture media, which were applied to cells from both human and mouse CFU-GM. In the second phase (Protocol Transfer), the SOPs were transferred to four laboratories to verify the linearity of the assay response and its inter-laboratory reproducibility. After a further phase (Protocol Performance), dedicated to a training set of six anticancer drugs (adriamycin, flavopindol, morpholino-doxorubicin, pyrazoloacridine, taxol and topotecan), a model for predicting neutropenia was verified. Results showed that the assay is linear under SOP conditions, and that the in vitro endpoints used by the clinical prediction model of neutropenia are highly reproducible within and between laboratories. As expected, both tests failed to accurately predict the human MTD of a drug that is a likely protoxicant. On the basis of these results, we proposed a formal Phase II validation study using the Test A SOP for 16-18 additional xenobiotics that represent the spectrum of haematotoxic potential.

Additional information

Authors: PESSINA A ET AL, a Institute of Microbiology, Milan (IT);ALBELLAB B, CIEMAT, Madrid (ES);BUEREN J, CIEMAT, Madrid (ES);BRANTOM P, TNO BIBRA International Ltd, Carshalton, (GB);CASATI S, European Commission, Joint Research Centre, Institute for Health and Consumer Protection, ECVAM, Ispra (IT);GRIBALDO L, European Commission, Joint Research Centre, Institute for Health and Consumer Protection, ECVAM, Ispra (IT);PARCHMENT R, Wayne State University, Detroit (USA);PARENT-MASSIN D, ESMISAB, Plouzane (FR);SIBIRIL Y, ESMISAB, Plouzane (FR);SCHOETERS G, VITO, Mol (BE);VAN DEN HEUVEL R, VITO, Mol (BE)
Bibliographic Reference: An article published in: Toxicology in Vitro, Volume 15, Issue 6, pp. 729-740, December 2001
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