Hematotoxicity

Vinca alkaloids (vincristine, vinblastine, vindesine) are derived from the periwinkle plant (Vinca rosea), they bind to tubulin and inhibit its polymerization into microtubules and spindle formation, thus producing metaphase arrest. They are cell cycle specific and interfere also with other cellular activities that involve microtubules, such as leukocyte phagocytosis, chemotaxis, and axonal transport in neurons. Vincristine is mainly neurotoxic and mildly hematotoxic, vinblastine is myelosuppressive with veiy low neurotoxicity whereas vindesine has both, moderate myelotoxicity and neurotoxicity. 

Parent-Massin D, Thouvenot D. 1993. In vitro study of pesticide hematotoxicity in human and rat progenitors. J Pharmacol Toxicol Methods 30 203-207. 

The model by Medinsky et al. (1995) considered the dosimetry of benzene and its metabolites in bone marrow in order to help explain their hematotoxic and myelotoxic effects. It is well known that none of the metabolites alone produces the effects seen with benzene exposure. Although it is not yet a fully developed PBPK model, this study lays the groundwork for further model development. 

Hydrolysis of the amide bond generally leads to inactivation of the substrate and accelerates excretion of the products. In the case of aminoacyl-anilides, however, such hydrolysis may represent a pathway of toxification, since it liberates aromatic amines, which are potentially hematotoxic, nephrotoxic, hepatotoxic, and/or carcinogenic. 

The role of deacetylation in methemoglobinemia induced by acetanilide (4.101) and phenacetin (4.107) has been demonstrated. Indeed, concomitant i.p. administration of BNPP considerably reduced the hematotoxicity of these compounds [87]. Recent studies have shown that /V-hydroxyphenetidine (4.144), a metabolite of deacetylated phenacetin, is responsible for hemolysis and methemoglobin formation [88]. 

A hydroxylamino product was also found to be the hematotoxic metabolite of the herbicide propanil (4.145) [89]. After administration of lidocaine (4.128, Fig. 4.5) to humans, 2,6-dimethylaniline-hemoglobin adducts were detected in blood. Again, an /V-hydroxylated metabolite appears to be involved [90],... 

The mechanisms of action for nephrotoxic (with the exception of 2. -globulin-mediated nephropathy specific to male rats) or hematotoxic effects have not been clearly delineated, and with the available information, it is difficult to speculate how 1,4-dichlorobenzene might cause such effects. More information concerning the mechanisms of action for blood and kidney effects are needed before methods for blocking those mechanism and reducing toxic effects can be developed. 

Goldstein BD Hematotoxicity in humans. In Laskin S, Goldstein BD Benzene toxicity. A critical evaluation. J Toxicol Environ Health Swpp/2 69-105, 1977... 

Toxieology. 2-Ethoxyethanol (EE) is of low acute toxicity, but repeated or chronic exposures have caused hematotoxic, fetotoxic, ter-... 

Dodson SM, Landreth KS, Piktel DA, et al Hematotoxic effects of prenatal exposure to heptachlor. Toxicologst 6Q )-2 S, 2001... 

Mercaptopurine [6-MP] (Purinethol) [Antineoplastic/ Antimeta lite] Uses Acute leukemias, 2nd-line Rx of CML NHL, maint ALL in children, immunosuppressant w/ autoimmune Dzs (Crohn Dz) Action Antimetabolite, mimics hypoxanthine Dose Adults. 80-100 mg/mVd or 2.5-5 mg/kg/d maint 1.5-2.5 mg/kg/d Peds. Per protocol X w/ renal/hepatic insuff on empty stomach Caution [D, ] Contra Severe hepatic Dz, BM suppression, PRG Disp Tabs SE Mild hematotox, mucositis, stomatitis, D rash, fever, eosinophilia, jaundice. Hep Interactions T Effects W/ allopurinol T risk of BM suppression W/ trimethoprim-sulfamethoxazole X effects OF warfarin EMS May falsely T glucose OD May cause NA and liver necrosis symptomatic and supportive Meropenem (Merrem) [Antibiotic/Carbapenem] Uses lntra-abd Infxns, bacterial meningitis Action Carbapenem X cell wall synth, a [3-lactam Dose Adults. 1 to 2 g IV q8h Peds. >3 mo, <50 kg 10-40 mg/kg IV q 8h in renal insuff Caution [B, ] Contra [3-Lactam sensitivity Disp Inj 500 mg, 1 g SE Less Sz potential than imipenem D, thrombocytopenia Interactions T Effects W/ probenecid EMS Monitor for signs of electrolyte disturbances and... 

Moore and Calabrese (1982) found no significant alterations in hematological parameters within groups of mice exposed to chlorine dioxide in the drinking water for 30 days, at a concentration that resulted in an estimated dose of 25 mg/kg/day. However, when similarly examining the hematotoxicity of chlorite, Moore and Calabrese (1982) found significant increases in mean corpuscular volume and osmotic fragility at a dose level of 19 mg/kg/day. 

More and more biomarkers and gene arrays have been identified and getting ready to enter the profiling portfolio to address organotypic toxicity. We refrain from detailed analysis here and refer the reader to the specific chapter addressing hepatotoxicity and hematotoxicity (Chapter 17). 

The main target organs for compound toxicity leading to either drug withdrawal or arrest of compound development as estimated in various studies [3], are classically pointing at liver, the cardiovascular system and bone marrow (hematotoxicity). Cardiovascular and hepatotoxicity were discussed in previous chapters and this chapter focuses on hematotoxicity. 

Hematotoxicity, defined as drug-induced altered production of peripheral blood cells, is most commonly associated with antiproliferative oncology compounds but is also caused by drugs for various indications, covering a wide pharmacology and chemical structure diversity (Table 17.1). This vast variety of chemical structures makes it difficult to predict hematotoxicity by in silica approaches and to model... 

Table17.1 Compoundsfrom difFerenttherapyareas, pharmacological classes and structures that induce hematotoxicity [59-63].

Table 17.1 lists non-oncology compounds from diverse therapeutic, chemical, pharmacological areas and structures that induce clinical hematotoxicity. This demonstrates that bone marrow toxicity is not restricted to a small number of pharmacological or structural classes, thereby making it more difficult to understand specific mechanisms of toxicity. However, there are three classes of mechanisms of hematotoxicity, including antiproliferative, immune-mediated and other. Immune-mediated hematotoxicity and other indirect toxicities (e.g., a decrease of erythropoietin in kidney, leading to an impeded red cell production in the bone marrow) are not discussed in detail in this chapter as it requires involvement of the immune system or remote interactions and in vitro profiling assays have not been developed to detect these 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]. 

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. 

Tier 1 assay qualification entailed (i) evaluating compounds known to induce lineage specific hematotoxicity (ii) comparing the results from the myeloid tier 1 assay to the mouse CFU-GM assay (iii) comparing the results from the erythroid tier 1 assay to reduction in peripheral blood reticulocytes. 

Qualification of the tier 1 assays with the limited number of compounds indicated that the cell lines were able to predict the in vivo hematotoxicity potential of compounds, but further qualification using more compounds and specifically noncytotoxic compounds are still required. 

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