Tiered Cascade of Testing

Primary or secondary pharmacology can influence hematopoiesis because hematopoietic and stromal cells express many different receptors that are also therapeutic targets, such as neurotransmitters [23-25], In the mouse, an HI receptor agonist antagonized the H2-induced increase of CFU-GM by its off-target effect at the latter receptor [26], Albeit this is not an example of direct hematotoxicity, it does demonstrate that therapeutic drugs bind to targets on hematopoietic and stromal cells and influence hematopoiesis. 

The last potential mechanism to be discussed in this chapter is drug-induced altered receptor expression. Hematopoiesis is a very intricate process that is regulated by cytokines and cell-cell interactions. Interruption with any of these processes can result in hematotoxicity. For example, zidovudine (AZT) decreases Epo [27], GM-CSFaand to lesser extent IL-3 receptor expression [7]. Decrease in the expression of the above receptors seems to lead to anemia and neutropenia, by decreasing the number of CFU-E and CFU-GM, respectively. 

Although not a mechanism of hematotoxicity, polymorphic metabolism of a compound needs to be discussed since polymorphism can be associated with clinical hematotoxicity. For several compounds [28-39], one of the polymorphic enzymes increases exposure to the toxic form of the compound and thereby induces hematotoxicity in the patient, due to higher exposure levels and not due to a specific mechanism of toxicity within the patient populations. 

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