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ToxSci Advance Access published online on July 7, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi250
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received May 24, 2005
Accepted July 5, 2005

In Vitro Toxicology

Validation and Development of a Predictive Paradigm for Hemotoxicology using a Multifunctional Bioluminescence Colony-Forming Proliferation Assay

Ivan N. Rich PhD1* and Karen M. Hall MT (ASCP)1

1 HemoGenix, Inc., Colorado Springs, CO 80907

* To whom correspondence should be addressed.
Ivan N. Rich, E-mail: ivannr{at}hemogenix.com


  Abstract

The lympho-hematopoietic colony-forming assay has been redesigned into a rapid, non-subjective and standardized proliferation assay that can measure the effects of compounds on multiple stem and progenitor cell populations from different species simultaneously using a sensitive, high-throughput bioluminescence readout. Eleven reference compounds from the Registry of Cytotoxicity (RC) and 8 other compounds, including anti-cancer drugs, were studied over a 8-9 log dose range for their effects on 7 cell populations from both human and mouse bone marrow simultaneously. The cell populations studied included a primitive (HPP-SP) and mature (CFC-GEMM) stem cell, 3 hematopoietic (BFU-E, GM-CFC, Mk-CFC) and 2 lymphopoietic (T-CFC, B-CFC) populations. The results reveal a 5-point prediction paradigm for lympho-hematotoxicity. Depending on how and which populations are affected, the resulting effects in the periphery can be predicted. Validation against the RC Prediction Model produces a high degree of correlation between the in vitro IC50 values and known in vivo LD50 values, thereby allowing pre-clinical dosing to be predicted. If primary human hematopoietic target tissue is used, inhibitory concentration (IC50/IC75/IC90) values of anti-cancer and other drugs can be converted into predicted clinical doses which, when compared to published chemotherapeutic dosing regimen, are very similar. When performed during early drug screening, the prediction value of the assay should help reduce time and cost, but above all, provide increase efficacy and safety for the patient.

The authors certify that all research involving human subjects was done under full compliance with all government policies and the Helsinki Declaration.


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