Depression Of Bone Marrow Function Research Articles

The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment

Detection, treatment, and prevention of bone marrow diseases have long been the aims of experimental and clinical hematologists and mechanistically oriented toxicologists. Among these diseases is aplastic anemia, which manifests as the cessation of normal blood cell production; the leukemias, in contrast, feature the production of excessive hematologic cancer cells. Both diseases are associated with exposure to either industrial chemicals or cancer chemotherapeutic agents. Studies of hematopoietic bone marrow cells in culture have shown that the generation of circulating blood cells requires the interaction of hematopoietic stem cells (HSCs) with supporting marrow stromal cells; yet, isolation of HSCs from bone destroys the unique morphology of the marrow stroma in which the HSCs reside. Imaging techniques and related studies have made it possible to examine specific niches where HSCs may either initiate differentiation toward mature blood cells or reside in a dormant state awaiting a signal to begin differentiation. HSCs and related cells may be highly vulnerable to the mutagenic or toxic effects of drugs or other chemicals early in these processes. Additional studies are required to determine the mechanisms by which drug or chemical exposure may affect these cells and lead to either depression of bone marrow function or to leukemia.

Anemia in patients with midgut carcinoid, treated with alpha interferon: effects by erythropoietin treatment on the perceived quality of life

One important side effect from alpha interferon is depression of bone marrow function and studies have shown that patients with carcinoid tumours treated with alpha interferon suffers from fatigue and impaired physical functions. The aim of this pilot study was to investigate if treatment with erythropoietin (EPO) could have a positive effect on self-rated quality of life (QoL). Eighteen patients with midgut carcinoid treated with alpha interferon were included in the study. There were statistical significant increases in haemoglobin (Hb) levels between baseline and 4 months, between baseline and 8 months as well as between baseline and 2-year follow-up. No EPO related side effects were reported. There were improvements of more than 10 points in self-rated QoL-issues related to anaemia. Even though the analysis did not reveal any statistically significant relation between the observed increase in Hb levels and self-rated QoL, this pilot study has increased the knowledge about benefits, doses and frequency of EPO treatment in patients with midgut carcinoid suffering from interferon related anaemia.

Differential expression of cytochrome P450 genes associated with benzene‐induced hematotoxicity

Benzene is an established human carcinogen and leukemogen. Chronic benzene exposure results in progressive depression of bone marrow function with increased risks of aplastic anemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), chronic lymphocytic leukemia, and other disorders. The mechanism underlying benzene toxicity remains uncertain; an initial metabolism and bioactivation of benzene, especially by CYP2E1 in the liver, was considered a prerequisite. To identify CYP genes whose expression is aberrant in benzene poisoning, a cDNA microarray containing 32 CYP genes was used to detect differential expression of CYPs in patients with hematopoietic dysfunction of benzene exposure. Seven female shoemakers with hematological disorders (six cases of decreased peripheral white blood cells and one case of aplastic anemia) were recruited, and seven age- and gender-matched normal subjects were selected as controls. Total RNA from the two groups was prepared, followed by reverse transcription to cDNAs with concomitant incorporation of fluorescent dCTP (Cy3 for the patients and Cy5 for the controls). Microassay was performed. Genes with a two-fold higher/lower expression level were considered to be significant. Six CYP genes (CYP4F3, CYP1A1, CYP27A1, CYP1B1, CYP2B6, and CYP51) were found to be differentially expressed between benzene-exposed patients and controls. Among these, CYP4F3 gene was up-regulated consistently among all patients. Our study indicated that CYP4F3 is up-regulated in peripheral blood cells in bezene poisoning and may serve as a new biomarker for the exposure and poisoning of benzene.

Treatment with High Dose [111In-DTPA-D-PHE1]-Octreotide in Patients with Neuroendocrine Tumors: Evaluation of Therapeutic and Toxic Effects

Carcinoid tumors and endocrine pancreatic tumors often express somatostatin receptors (sst). Tumor spread may be visualized by sst scintigraphy using [111In-DTPA-D-Phe1]-octreotide. In this study, tumor targeting therapy with [111In-DTPA-D-Phe1]-octreotide at high doses (6 GBq every third week) was used to treat patients with sst-expressing tumors. Five patients entered the protocol and three were evaluable for response, while all could be evaluated for toxicity. Two patient responded with a significant reduction in tumor markers (>50%). The third patient showed increasing levels of tumor markers. Side effects were expressed as depression of bone-marrow function. In one patient a grade 4 reduction in platelet count was observed requiring several thrombocyte transfusions. In another two patients platelet counts decreased significantly. We conclude that treatment with [111In-DTPA-D-Phe1]-octreotide can be used in patients with neuroendocrine tumors but blood parameters have to be carefully monitored to avoid severe side effects.

Rational design of novel immunosuppressive drugs: analogues of azathioprine lacking the 6-mercaptopurine substituent retain or have enhanced immunosuppressive effects.

Clinical use of the immunosuppressive drug azathioprine is limited by potentially serious toxic effects related to depression of bone marrow function. The immunosuppressive and toxic properties of azathioprine are regarded as being properties of the cytotoxicity of its metabolite, 6-mercaptopurine (6-MP). However, azathioprine has an immunosuppressive effect additional to that attributable to 6-MP alone, and we propose that this is associated with an action of the methylnitroimidazolyl substituent. This suggests a route to the rational design of nontoxic immunosuppressants by replacing the 6-MP component of azathioprine with nontoxic thiols. We have synthesized and tested in vitro 24 such analogues, with two being further tested in vivo. In the human mixed lymphocyte reaction, virtually all compounds showed some degree of activity, 10 compounds being more active than azathioprine. In vivo, two compounds were more effective than azathioprine at prolonging graft survival in mice. In an oral toxicity study in male CD1 mice at doses equivalent to those at which azathioprine caused severe bone marrow depression both analogues had no toxic effects. Our results show that the immunosuppressive effects and bone marrow toxicity of azathioprine are not a consequence of release of 6-MP alone, and with appropriate modification can be separated, an approach which may lead to less toxic immunosuppressive drugs.

Eflornithine for the Treatment of Pneumocystis carinii Pneumonia in Patients with the Acquired Immunodeficiency Syndrome: A Preliminary Review

Pneumocystis carinii pneumonia (PCP) is the most common opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). Eflornithine is an antiprotozoal agent active against P. carinii. It acts by inhibiting ornithine decarboxylase, an enzyme that is essential for cellular function. The drug is initially administered intravenously, followed by oral therapy. Eflornithine has been used on a compassionate basis in AIDS patients with PCP who were intolerant of or unresponsive to traditional agents. Overall, the response rate has been about 35%; however, conclusions are difficult to make since patients had different stages of disease and received treatment for varying periods of time. Side effects include depression of bone marrow function, diarrhea, hearing loss, seizures, alterations in liver function tests, and rash. While the need for safer and more efficacious antipneumocystis drugs grows, widespread use of seemingly promising agents should be based on well-conducted clinical trials.

Chemical of current interest--benzene.

Benzene is one of the world's major commodity chemicals. It is derived from petroleum and coal and is used both as a solvent and as a starting material in chemical syntheses. The numerous industrial uses of benzene over the last century need not be recounted here, but the most recent addition to the list of uses of benzene is as a component in a mixture of aromatic compounds added to gasoline for the purpose of replacing lead compounds as anti-knock ingredients. The best known and longest recognized toxic effect of benzene is the depression of bone marrow function seen in occupationally exposed individuals. These people have been found to display anemia, leucopenia, and/or thrombocytopenia. When pancytopenia, i.e., the simultaneous depression of all three cell types, occurs and is accompanied by bone marrow necrosis, the syndrome is called aplastic anemia. In addition to observing this decrease in humans and relating it to benzene exposure, it has been possible to establish animal models which mimic the human disease. The result has been considerable scientific investigation into the mechanism of benzene toxicity. Although the association between benzene exposure and aplastic anemia has been recognized and accepted throughout most of this century, it is only recently that leukemia, particularly of the acute myelogenous type, has been related to benzene. The acceptance of benzene as an etiological agent in aplastic anemia in large measure derives from our ability to reproduce the disease in most animals treated with sufficiently high doses of benzene over the necessary time period. Unfortunately, despite extensive efforts in several laboratories, it has not been possible to establish a reproducible, reliable model for the study of benzene-induced leukemia. The recent demonstration that several animals exposed to benzene either by inhalation or in the drinking water during studies by Drs. B. Goldstein and C. Maltoni suggests that such a model may be forthcoming. Nevertheless, at this time it is not clear whether bone marrow damage of the type that leads to aplastic anemia is required for the development of leukemia. Most studies of benzene toxicity have involved dosing animals with benzene either by inhalation or by injection, using high doses to ensure a toxic response. Very few studies have concentrated on the oral route of administration and none have concentrated on administering benzene by mouth at the low doses occasionally detected in drinking water.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of strain differences in mice on the metabolism and toxicity of benzene

Chronic benzene exposure results in a progressive depression of bone marrow function and is thought to be caused by a metabolite of benzene ( Snyder and Kocsis, 1975; Goldstein and Laskin, 1977). Several reports concerning differences in xenobiotic metabolism and toxicity among inbred strains of mice prompted us to study benzene metabolism and toxicity in C57BL 6 and DBA 2 mice. DBA 2 mice were more susceptible to benzene than C57BL 6 mice. No differences in the total amount of urinary benzene metabolites produced were found between the strains; however, differences in the relative amounts of specific metabolites were noted. DBA 2 mice produced more phenylglucuronide but less ethereal sulfate conjugates than C57BL 6 mice. Hydrolysis of the urinary conjugates revealed that DBA 2 mice excreted more phenol, but less hydroquinone than C57BL 6 mice. Multiple dose studies revealed that the more resistant C57BL 6 mice contained less water soluble benzene metabolites in bone marrow, liver, kidney, blood, spleen, and lung than DBA 2 mice. C57BL 6 mice also contained less covalently bound metabolites in bone marrow, blood, spleen, and muscle than DBA 2 mice following multiple doses of benzene. V max values for UDPGA utilization in C57BL 6 mice were almost six times the V max values observed for DBA 2 mice. Furthermore, V max values for phenylsulfate formation in C57BL 6 mice were three times the V max values for DBA 2 mice. It was concluded that the difference in susceptibility to benzene between C57BL 6 and DBA 2 mice was not the result of a single factor, buth rather, the sum total of a number of metabolic events.

Chloramphenicol

After chloramphenicol was marketed in 1949, its broad spectrum of activity and therapeutic efficacy were quickly appreciated and led to widespread use. However, from 1950 to 1952, numerous reports appeared suggesting a causal relationship between its use and the development of aplastic anemia and pancytopenia. In 1955, Krakoff et al 1 showed that large dosages (6 to 12 g/day) of chloramphenicol led to a disappearance of reticulocytes and anemia in all four patients to whom they administered the drug and vacuolation of erythrocyte precursors and a reversible pancytopenia in one of these patients. Subsequently, it became clear that chloramphenicol somtimes caused a dose-related depression of bone marrow function in patients who received the drug. Rarely, an idiosyncratic aplasia of the marrow occurred. 2 The former is reversible, whereas the latter is usually fatal. Other than bone marrow toxicity, chloramphenicol has been shown to cause the gray baby syndrome, 3 depression

Differential susceptibility of mouse lymphocytes to an immunosuppressant from group A streptococci

Cytoplasmic components (SF) of group A streptococcus have been shown to suppress the immune response. Lymphocytes exhibit a differential susceptibility to these components when several functional criteria are applied. PFC appear to be more susceptible than RFC suggesting that the long-lived, undifferentiated lymphocytes that form rosettes escape the effects of SF, but antibody-forming cells are suppressed. Similarly, thymic dependent functions such as PHA responsiveness, mixed lymphocye interaction, and synergism with bone marrow are unaffected. Bone marrow functions, such as hematopoiesis and the ability to synergize with normal thymus, however, are suppressed by SF pretreatment. SF, furthermore, causes a loss of lymphocytic cells from marrow, and a depression of in vitro proliferative capacity. These results indicate that SF is immunosuppressive due to a selective depression of bone marrow function.

Hypersensitivity to Nitrogen Mustards in the Form of Erythema Multiforme

Nitrogen mustard preparations have an established role in the treatment of Hodgkin's disease. 1,2 They may be used in conjunction with radiation therapy or alone to ameliorate constitutional symptoms. Although the beneficial response to such therapy may be dramatic at first, after variable periods symptoms always return. Several serious toxic side effects may follow the administration of a nitrogen mustard. This and similar agents inhibit cell growth and damage rapidly proliferating tissue forming the basis of their therapeutic action. Unfortunately, normal tissue is as susceptible as neoplastic. Severe local reactions may develop from the extravasation of a nitrogen mustard into the subcutaneous tissues. Veins used for injection of concentrated solutions of mustard are subject to the development of thrombophlebitis. Systemic reaction include nausea and vomiting, depression of bone marrow function, destruction of lymphoid tissue and, rarely, skin eruption. Both herpes zoster and maculopapular reactions apparently unrelated to hypersensitivity have been observed. 3

Stimulation of Hematopoiesis by Androgenic Hormone.

Excerpt Androgenic hormone increases erythropoiesis when administered in massive doses for a prolonged period. Furthermore, in depression of bone marrow function by toxic agents or disease, improve...

Protection by diethyldioxystilbenedipropionate against leucopenia due to roentgen therapy

LEUCOPENIA resulting from roentgen therapy, associated, as it is, with dangers to the patient, often necessitates the interruption of a course of treatment before the desired dose has been reached. Work on the protection of the leucopoietic function from the effects of the ionizing radiation is therefore well worth while. In the following short review of the experimental work in this field we shall consider only those authors who have mostly concerned themselves with this subject and the principal drugs used. Patt and his co-workers (i949, i95o a, b) have observed that rats pre-treated with cysteine suffer a smaller reduction in the number of circulating leucocytes, especially of the granular series, than do the control animals. Gaffaratti (I95i), on the other hand, has not demonstrated any protective action on leucopoiesis by administering cysteine and ascorbic acid together to animals given radiation to the whole body. Chapman and his co-workers (195o) and other authors (Barron and Flood, 195o ; Cronkite, Brecher, and Chapman, 1951 ) found that glutathione in their experiments had a protective action similar to that found by Patt for cysteine. Folic acid has no influence on the blood-picture or on the duration of survival of irradiated pigs ; Goldfeder, Cohen, Miller, and Singer (1948) found a reduced mortality, but no protection of the leucopoietic function by folic acid. Cyanides do not prevent changes in the marrow or in lymph-nodes, but they provoke a quicker regeneration of h~emopoietic tissues than in the controls. Treadwell, Gardner, and Lawrence (1943) observed a reduced mortality in irradiated rats pretreated with ~estradiol benzoate as compared with rats not so treated ; while Part and his colleagues (i949) showed that pre-treatment with the same drug afforded protection against reduction of the polym0rphonuclear leucocytes by irradiation. Vitamins C, B6, B12, whether given preventatively or therapeutically, have produced contradictory and unconvincing results and Levitt (1955) has found no increase in the count following administration of pentanucleotides to patients undergoing ' large volume radiotherapy' with a white-cell count as low as i4oo/cu.mm. He emphasizes that at present we have no drug able to protect the leucopoietic system from damage by X rays. Regarding the pathogenesis of the leucopenia due to radiation there are still doubts and remarkable discrepancies. Several authors maintain that the leucopenia is due solely to the cytostatic action of the radiation on the bone-marrow, while others consider that it is due to direct action of the radiation on the circulating leucocytes and that the depression of bone-marrow function is secondary to toxic substances set free by damaged leucocytes and cells of other tissues. Most authors, however, consider that both mechanisms participate in producing radiation leucopenia. Recently Storti and his colleagues (1954, 1955) using a new criterion (leucocyte resistance*) have made possible a wide and more complete interpretation of the mechanism of leucopenia due to antimitotics and have suggested a means of preventing and treating leucopenia. As a result of their researches it is possible to say that many physical and chemical agents render mature

Triethylene Melamine in the Treatment of Neoplastic Disease

Triethylene Melamine in the Treatment of Neoplastic Disease