Hematopoietic

Cadmium will affect tumors of the hematopoietic system in rodents. In mice infected with murine lymphocytic leukemia virus, oral cadmium increases the incidence of lymphocytic leukemia (Blakley 1986). It is suspected that cadmium-induced reduction in immunosurveillance allows emergence of leukemia. Subcutaneous doses of cadmium will also induce lymphoma in mice in a strain-dependent manner (Waalkes et al. 1994 Waalkes and Rehm 1994). Dietary cadmium exposure in Wistar rats will cause dose-related increases in large granular lymphocyte (LGL) leukemia (Waalkes et al. 1992b). In contrast, a single high-dose subcutaneous injection of cadmium will markedly decrease the spontaneous incidence of LGL leukemia in Fischer rats (Waalkes et al. 1991a). A reduction in spontaneous lymphoma incidence can also occur in hamsters treated with cadmium (Waalkes et al. 1994). 

In early 1987 we proved that the bryostatins were capable of stimulating normal bone marrow progenitor cells to form colonies in vitro and to activate neutrophils (68). Bryostatin 1, e.g., promotes many of the biological effects of GM-CSF and this remarkable activity combined with its antineoplastic activity make it a very attractive clinical candidate. Meanwhile, bryostatins 1 and 2 have found an important role as biochemical probes for unraveling the mechanisms of normal hematopoiesis (69). An important advance here was the observation that bryostatin 1 will stimulate normal erythropoiesis in human bone marrow progenitor assays. Furthermore, bryostatin 1 approximated the stimulatory effects of IL-3 on both murine normal and w/w bone marrow 

Preliminary evaluation of bryostatins 1 and 2 against several microbial systems proved to be negative. However, bryostatin 1 was found to inhibit induction of Epstein-Barr virus in Raji cells, a potentially important lead along with its GM-CSF and IL-3 activity to a possible application in HIV-1 therapy. However, only a clinical trial will provide a definitive answer to this proposal. 

---

Cytokines, eg, interferons, interleukins, tumor necrosis factor (TNF), and certain growth factors, could have antitumor activity directiy, or may modulate cellular mechanisms of antitumor activity (2). Cytokines may be used to influence the proliferation and differentiation of T-ceUs, B-ceUs, macrophage—monocyte, myeloid, or other hematopoietic cells. Alternatively, the induction of interferon release may represent an important approach for synthetic—medicinal chemistry, to search for effective antiinflammatory and antifibrotic agents. Inducers of interferon release may also be useful for lepromatous leprosy and chronic granulomatous disease. The potential cytokine and cytokine-related therapeutic approaches to treatment of disease are summarized in Table 4. A combination of cytokines is a feasible modaUty for treatment of immunologically related diseases however, there are dangers inherent in such an approach, as shown by the induction of lethal disserninated intravascular coagulation in mice adrninistered TNF-a and IFN-y. 

Physiological Classifications of Contaminants. The physiological classification of air contaminants is difficult, because the type of action of many gases and vapors depends on concentrations (55). For example, a vapor at one concentration may exert its principal effect as an anesthetic but, at a lower concentration, the same vapor may iujure the nervous system, the hematopoietic (blood-forming) system, or some visceral organ (see Toxicology). 

Fohc acid is a precursor of several important enzyme cofactors required for the synthesis of nucleic acids (qv) and the metaboHsm of certain amino acids. Fohc acid deficiency results in an inabiUty to produce deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and certain proteins (qv). Megaloblastic anemia is a common symptom of folate deficiency owing to rapid red blood cell turnover and the high metaboHc requirement of hematopoietic tissue. One of the clinical signs of acute folate deficiency includes a red and painhil tongue. Vitamin B 2 folate share a common metaboHc pathway, the methionine synthase reaction. Therefore a differential diagnosis is required to measure foHc acid deficiency because both foHc acid and vitamin B 2 deficiency cause... 

Deficiency. Macrocytic anemia, megaloblastic anemia, and neurological symptoms characterize vitamin B 2 deficiency. Alterations in hematopoiesis occur because of the high requirement for vitamin B 2 for normal DNA repHcation necessary to sustain the rapid turnover of the erythrocytes. Abnormal DNA repHcation secondary to vitamin B 2 deficiency produces a defect in the nuclear maturational process of committed hematopoietic stem cells. As a result, the erythrocytes are either morphologically abnormal or die during development. 

Frequendy, the treatment of helminthic diseases requites adjunct medication. Allergic reactions are commonly seen as a result of tissue invasion by worms or as a consequence of anthelmintic therapy. Antihistamines and corticosteroids may be necessary adjuncts to therapy. Anemia, indigestion, and secondary bacterial infections can also occur and may requite concomitant therapy with hematopoietic drugs and appropriate antibiotics. 

D. Agents which act on the blood or hematopoietic system Decreases hemoglobin function deprive body tissues of oxygen ... 

British investigators (Haddow and Timmis 1951) synthesized and studied esters of the methanesulfonic acid. The most active derivative was the dimethylsulfonic ester of 1,4-butanedione, known as busulfan. Busulfan interacts with the thiol groups of proteins and amino acids some of its metabolites can alkylate the thiols of cysteine, peptides and proteins. Busulfan exerts selective cytotoxic activity in hematopoietic bone marrow cells and inhibits the formation of granulocytes and platelets. It slightly affects the lymphoid tissue. 

The CaR regulates numerous biological processes, including the expression of various genes (e.g., PTH) the secretion of hormones (PTH and calcitonin), cytokines (MCP-1), and calcium (e.g., into breast milk) the activities of channels (potassium channels) and transporters (aquaporin-2) cellular shape, motility (of macrophages), and migration cellular adhesion (of hematopoietic stem cells) and cellular proliferation (of colonocytes), differentiation (of keratinocytes), and apoptosis (of H-500 ley dig cancer cells) [3]. 

Cytokine receptors are a group of structurally related receptors, which couple to the JAK-STAT pathway. Cytokine receptors function as homodimers or heterooligomers. They are divided into two main subclasses, class I, which contains receptors for a variety of hematopoietic growth factors and interleukins and class II, which contains receptors for interferons and interleukins 10, 20/24 and 22. 

Hematopoietic cytokines/colony-stimulating factors IL-3, IL-5, IL-6, IL-7, erythropoietin, GM-CSF, G-CSF, M-CSF, thrombo-poietin... 

Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

To circumvent this problem, vectors that are based on lentiviruses have been developed. In contrast to prototypic retroviruses, lentiviruses do not require cell division for integration. Gene-therapy vectors have been developed from a broad spectrum of lentiviruses including human immunodeficiency vims (HIV), simian and feline immunodeficiency vims as well as visna/maedi vims. The most widely used lentiviral vector system is based on HIV-1. These vectors can efficiently transduce a broad spectrum of dividing and nondividing cells including neurons, hepatocytes, muscle cells, and hematopoietic stem cells [1,2]. 

Hemangioblasts are the bipotential precursor cell population from which hematopoietic and angioblastic cells arise. 

Colony-stimulating factors Hematopoietic colony-stimulating factors... 

Hematopoietic (blood) cells transport oxygen and carbon dioxide, contribute to host immunity, and facilitate blood clotting [1], A complex, interrelated, and multistep process, called hematopoiesis, controls the production as well as the development of specific marrow cells from immature precursor cells to functional mature blood cells. This well-regulated process also allows for replacement of cells lost through daily physiologic activities. The proliferation of precursor cells, the maturation of these into mature cells, and the survival of hematopoietic cells require the presence of specific growth factors. 

All mature blood cells arise from primitive hematopoietic cells in the bone marrow, the pluripotent stem cells. Approximately 0.1% of the nucleated cells of the bone marrow are pluripotent stem cells and approximately 5% of these cells may be actively cycling at any one time. The stem cell pool maintains itself through a process of asymmetrical cell division when a stem cell divides, one daughter cell remains a stem cell and the other becomes a committed colony-forming cell (CFC). The proliferation and differentiation of CFCs are controlled by hematopoietic growth factors. The hematopoietic growth factors stimulate cell division, differentiation and maturation, and convert the dividing cells into a population of terminally differentiated functional cells. 

Ten types of mature blood cells have been identified each one is derived from primitive hematopoietic stem cells in the bone marrow erythrocytes (red blood cells) ... 

---