Known Compounds with Hematotoxic Potential

Antiproliferative compounds are easily detected using cell line or colonyforming unit (CPU) assays. Some of the potential mechanisms of non-antipro-liferative compounds leading to bone marrow toxicity include mitochondrial dysfunction [5, 6], aromatic hydrocarbon receptor (AhR) activation, receptor-mediated, altered receptor expression [7] and reactive intermediates [8, 9], but this list may grow with additional research as the mechanism(s) leading to bone marrow toxicity is still unknown for many compounds and will require significant amount of effort to elucidate. The next paragraphs briefly describe these potential mechanisms. 

In many ways, mitochondria resemble bacteria for example, the mitochondrial ribosomal RNA genes of all eukaryotes have been traced back to the eubacteria [10]. This can explain why some antibacterial compounds with the target of inhibiting bacterial protein synthesis also inhibit mitochondrial protein synthesis [6, 11, 12], resulting in hematotoxicity. Tetracycline, chloramphemcol and some oxazolidinone antibiotics have been shown to induce hematotoxicity by inhibiting mitochondrial protein synthesis [13]. 

The AhR is expressed in bone marrow stromal cells [14] and human hematopoietic stem cells [15] and upon agonist binding the receptor translocates to the nucleus, resulting in altered transcriptional expression such as increased CYPlAl [16] and resulting in reactive oxygen species [17]. Nonpharmaceutical compounds such as TCDD, benzo(a)pyrene and benzene have been shown to induce hematotoxicity using this mechanism in vivo and in vitro [18, 19]. 

In addition to oxygen free radicals, other compounds such a clozapine, olanzapine and procainamide induce reactive intermediates [8, 9]. Clozapine and olanzapine bioactivation is thought to occur through a nitrenium ion [20] however clozapine but not olanzapine induce toxicity to neutrophils. This can lead to an immune-mediated depletion of neutrophils and their precursors (CFU-GM) [21]. Also, nonsteroidal antiinflammatory drugs (NSAIDs) have pro-oxidant radicals that when metabolized could cause oxidative stress [22]. 

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