Bone marrow with cytotoxic drugs

Changing the distribution of a drug can lead to toxic effects not described before. It is possible that after liposomal delivery high concentrations of drugs (e.g., cytotoxic drugs) inside macrophages affect these cells detrimentally (Poste and Kirsch, 1983). This results in toxic effects in liver, spleen, and bone marrow which were not previously associated with the use of these drugs. 

The inhibitors available for human use, azacitidine and decitabine, have been approved for the treatment of myelodysplastic syndrome (MDS) [98, 99[. MDS summarizes a set of different conditions that affect the maturation of blood cells. It is a group of bone marrow stem cell malignancies that have a pathogenetic overlap with acute myeloid leukemia, show peripheral blood cytopenias and, in more advanced subtypes, varied degrees of maturation arrest [100]. Both drugs are approved for all subtypes of MDS. Response rates are usually around 30%. The question whether the clinical benefit results more from epigenetic effects and re-activation of silenced maturation factors or more from cytotoxic effects on the immature hyperproliferative cells remains open. 

A major cause of morbidity and mortality in patients who receive cytotoxic treatment or radiotherapy for cancer is bacterial and fungal infections. Intensive chemotherapy is associated with fever and infection, and the development of neutropenia further increases this risk of infection. Consequently, maximum doses of some cytotoxic drugs are limited due to bone marrow toxicity. Higher doses of chemotherapy and radiation therapy have become possible due to a reduction in bone marrow damage with the availability of the CSFs for clinical use. 

Effects of G-CSF (color) or placebo (black line) on absolute neutrophil count (ANC) after cytotoxic chemotherapy for lung cancer. Doses of chemotherapeutic drugs were administered on days 1 and 3. G-CSF or placebo injections were started on day 4 and continued daily through day 12 or 16. The first peak in ANC reflects the recruitment of mature cells by G-CSF. The second peak reflects a marked increase in new neutrophil production by the bone marrow under stimulation by G-CSF. Treated patients in this study had fewer days of neutropenia, days of antibiotic treatment, and days of hospitalization. They also had a lower incidence of infections. (Normal ANC is 2.2-8.6 x 109/L.) (Modified and reproduced, with permission, from Crawford et al Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991 325 164.)... 

Further studies have validated this hypothesis, in part,4 and ultimately this inventive premise was borne out in clinical practice. As a result, 5-FU (5) was eventually approved for treatment of solid tumors, such as breast, colorectal, and gastric cancers. Marketed as Adrucil when administered intravenously, 5-FU can be used either as monotherapy or combination therapy with various cytotoxic drugs and biochemical modulators, such as leucovorin and methotrexate.5 Because 5-fluorouracil is not orally bioavailable, it must be administered by continuous infusion to optimize its efficacy due to its short half-life in plasma. In addition, 5-FU has poor selectivity toward tumors in vivo, and its distribution into tissues such as bone marrow, the gastrointestinal tract, the liver and skin causes high incidences of toxicity. In addition, in spite of its limited lipid solubility, 5-fluorouracil diffuses readily across the blood-brain barrier into cerebrospinal fluid and brain tissue.1,5... 

Apart from the standard general toxicities associated with cytotoxic chemotherapy such as bone marrow suppression, nausea, diarrhoea, stomatitis and alopecia, other drug-specific toxicities may occur, including the following. 

Busulfan is a potent cytotoxic drug. Early in development of the compound, in vivo experiments indicated that busulfan caused severe depression in the bone marrow. The most prevalent acute toxic effects associated with busulfan in animals are severe pancytopenia from bone marrow failure. Associated in vivo experiments show bone marrow aplasia, stromal cell damage, immunosuppression (impaired T-lymph-ocyte function), and pronounced adverse effects on reproductive glands, germ cells, and fertility in animals (lowest effective dose tested was 2 mg kg... 

As a therapeutic agent, mechlorethamine has many toxic effects. Acutely, it causes nausea and vomiting, skin blistering, and ulceration. After a week or two, it causes leukopenia, lymphopenia, anemia, thrombocytopenia, diarrhea, oral ulcers, and hyperuricemia. It can cause sterility and after a few years, leukemia. The most susceptible tissues are those with renewable cell populations, bone marrow, lymphoid tissues, and gastrointestinal (GI) epithelium. The therapeutic dose of mechlorethamine and most of the cytotoxic chemotherapy drugs is very close to the toxic dose. The therapeutic index (ratio of beneficial effect to toxic effect) is small. 

Drugs for which concentration assays are clearly unsuited include acute therapies (i.e. not used at steady state), those with extraordinarily short half-times (e.g. injected or intranasal polypeptides) and those for which either treatment is indicated regardless (late acetaminophen/parace-tamol overdoses, see above), or when adverse events are almost automatic and should be monitored in other ways, for example CNS toxicity with salicylates (see above) or liability to bone marrow suppression with cytotoxic agents. Furthermore, the efficacy and tolerability of some drugs are known to be unrelated to circulating concentrations (e.g. penicillin anaphylaxis),... 

Toxic effects with all cytotoxic drugs are severe nausea and vomiting, hair loss and bone marrow depression. 

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