Marrow toxicity

Dactinomycin, an antineoplastic dmg, was discovered in 1943 and is made in rather pure form by StreptomjcesparvuUus. Dactinomycin has some bacteriostatic antibacterial and antifungal activity, but high toxicity limits its use to antineoplastic therapy. It may be used alone or with other antineoplastics, with or without surgery and synergistic x-ray therapy. Dose limiting bone marrow toxicity may result in low white cell and platelet count. Intestinal mucosal damage also occurs. Reviews of more detailed chemotherapeutic information are available (217—222). 

Newer bleomycins such as peplomycin and especially liblomycin, are more resistant to bleomycin hydrolase. This results in less lung toxicity but more bone marrow toxicity, and allows for a different spectmm of antitumor action. Bleomycin is inactive orally it is given intravenously, intramuscularly, subcutaneously, or directiy into a cavity such as the pleural cavity. The majority of dmg is excreted unchanged in the urine. 

Pyrazolone derivatives are analgesic substances that have been known for a long time. The use of antipyrine (phenazone) and aminopyrine was sharply curtailed after their bone marrow toxicity was reported. Other derivatives, however, like phenylbutazone. 

DNA damage by trans-2,4-NjP-, (NC H ) (NHMe) occurs via cross-linking while with trans-2,6-N P (NC H ) (NHMe) both single strand breaking and cross-linking occurs. Although cumulative bone marrow toxicity induced by 2,2-N P2(IK H)4(pYr)2 (Pyr=pyrroli-... 

Since HU needs to be taken lifelong in the treatment of non-neoplastic conditions such as SCA (since the inhibition of ribonucleotide reductase is reversible) a major concern is its long term secondary effects. Several studies have shown the potential leukomegenic effect of HU in myeloproliferative disorders [22], [23]. Such concern becomes quite legitimate in sickle cell patients with permanently expanded erythropoiesis in whom the use of HU is at the limit of marrow toxicity. Hence alternative therapies must be sought for. 

The drug may cause liver toxicity and is contraindicated in patients with preexisting liver disease. The ALT should be monitored monthly initially and periodically thereafter. Leflunomide may cause bone marrow toxicity a complete blood cell count with platelets is recommended monthly for 6 months and then every 6 to 8 weeks thereafter. It is teratogenic and should be avoided during pregnancy. 

Hydroxyurea inhibits cell synthesis in the S phase of the DNA cycle. It is used selectively in the treatment of psoriasis, especially in those with liver disease who would be at risk of adverse effects with other agents. However, it is less effective than methotrexate. The typical dose is 1 g/day, with a gradual increase to 2 g/day as needed and as tolerated. Adverse effects include bone marrow toxicity with leukopenia or thrombocytopenia, cutaneous reactions, leg ulcers, and megaloblastic anemia. 

Kerstens, P. J., Stolk, J. N., De Abreu, R. A., Lambooy, L. H., van de Putte, L. B., and Boerbooms, A. A. (1995) Azathiopiine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis and Rheumatism. 38, 142-145. 

Cytotoxic drugs ore most toxic to rapidly proliferating cells, such as the intestinal mucosa, mucous membranes, skin, hair and bone marrow, leading to nausea and vomiting, stomatitis, alopecia and bone marrow toxicity. 

Carbutamide was the first oral anti-diabetic, and the prototype for the sul-phonamide type of agent. Carbutamide caused marked bone marrow toxicity in man, but derivatives of this, not containing the anilino function, such as tolbutamide... 

Fig. 8.15 Structures of carbutamide an oral anti-diabetic, associated with bone marrow toxicity, and tolbutamide a tOlbutamida compound without similar effects.

Chloramphenicol Serum iron levels may be increased because of decreased iron clearance and erythropoiesis due to direct bone marrow toxicity from chloramphenicol. 

Bone marrow toxicity Peginterferon alfa-2a suppresses bone marrow function and may result in severe cytopenias. Ribavirin may potentiate the neutropenia and lymphopenia induced by alpha interferons including peginterferon alfa-2a. Alpha interferons may be associated with aplastic anemia very rarely. 

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. 

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. 

To screen for bone marrow toxicity early in drug discovery, assays must be able to evaluate hundreds of compounds, be inexpensive, report results within two weeks (in order to impact chemistry cycle times) and be able to detect toxicity irrespective of cytotoxic or cytostatic mechanisms. Only cell line-based assays can meet all of these various criteria. 

Table 17.2 Tier 1 assay conditions. Cell lines and optimal culture conditions for evaluating bone marrow toxicity potential of compounds early in drug discovery. The adherent cell lines M2-10B4 and HepC2 are allowed to adhere to plates (preculture time) prior to addition of test compound. Relative cell number within a well is evaluated afterthe culture time using CellTiter Clo.

Tier 3 is the evaluation of bone marrow after in vivo exposure to determine in vivo applicability of the in vitro results (tiers 1 and 2) and predict clinical target- and chemistry-related toxidties. Historically, the bone marrow toxicity potential of compounds was evaluated by microscopic assessment of rat bone marrow cellularity from decalcified sternum bone slides, hematology and in some cases bone marrow differentials [55] only when a compound reached development. 

There is a high prevalence of bone marrow toxicity with antiproliferative oncology compounds that also occurs with many non-antiproliferative compound classes but at a much lower prevalence. It is these non-antiproliferative compounds that are of greatest... 

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