In vitro hematotoxicity testing in drug development: a review of past, present and future applications

Conventional hematotoxicity testing usually begins at the preclinical studies stage, and is valuable for monitoring the clinical status of subjects in clinical trials. However, as it is based on mature blood elements and related parameters, and not the cells producing these elements, it is not predictive. All proliferating cell systems, including lympho-hematopoiesis, exhibit a similar organizational structure that includes stem cells and their immediate progeny, the progenitor cells. These populations are the dose-limiting target populations for most drugs, especially anticancer drugs, as well as other compounds. In vitro assays detecting stem and progenitor cell populations are highly predictive, and new high-throughout colony-forming assays using human hematopoietic tissue allow hematotoxicity testing to be performed throughout drug development. Chronotoxicology and chronotherapeutics constitute a special application, and can predict the best time of the day to administer anticancer drugs.