Fanconi anemia

In the past, large doses of androgens were employed in the treatment of refractory anemias such as aplastic anemia, Fanconi s anemia, sickle cell anemia, myelofibrosis, and hemolytic anemias. Recombinant erythropoietin has largely replaced androgens for this purpose. 

There are several acquired hematological disorders which have an increased synthesis of Hb-F [summarized in (H37, K13)], Thus, an elevated level of Hb-F is frequently observed in, for example, Fanconi s anemia, megaloblastic anemia, polycythemia vera, various types of leukemia, multiple myeloma and lymphomas, macroglobulinemia, and metastatic disease of the bone marrow. The chemical heterogeneity of the Hb-F in some of these disorders (aplastic anemia, Fanconi s anemia, and various forms of leukemia) has been studied (H60, R29). In many instances, the to ratio is similar to that found in the normal newborn. This is particularly striking for patients with various forms of leukemia, and the Hb-F which is produced in increased quantities in these disorders invariably has a °y to y ratio of about 3 1. This newborn ratio of °y to y chains in Hb-F may be a common factor in these diseases as perhaps another example of fetal characteristics in red cells of patients with leukemia, it supports the hypothesis that these cells may be of fetal origin (H25). 

In patients with ataxia-telangiectasia, an autosomal recessive disease in humans resulting in the development of cerebellar ataxia and lymphoreticular neoplasms, there appears to exist an increased sensitivity to damage by x-ray. Patients with Fanconi s anemia, an autosomal recessive anemia characterized also by an increased frequency of cancer and by chromosomal instability, probably have defective repair of cross-linking damage. 

Down s syndrome Bloom s syndrome Fanconi s anemia Klinefelter s syndrome Ataxia telangiectasia Langerhans cell histiocytosis Shwachman s syndrome Severe combined... 

Other diseases Autoimmune diseases Amyloidosis Aplastic anemia Paroxysmal nocturnal hemoglobinuria Fanconi s anemia Thalassemia major Sickle cell anemia Severe combined immunodeficiency Inborn errors of metabolism... 

In accord with in vitro studies we should expect that the in vivo effects of MFs must have been the damaging ones. There are only few experimental in vivo and ex vivo studies, which, nonetheless, support this suggestion. Recently, we have showed for the first time (personal communication by LG Korkina, IB Deeva, IB Afanas ev) that MF effects may be much greater under pathophysiological than physiological conditions. We have studied the effects of a weak alternative magnetic field on leukocytes from Fanconi anemia (FA) patients, compared to... 

MF effects on FA relatives and healthy donors. (Fanconi anemia is an autosomal recessive disease associated with the overproduction of free radicals, Chapter 31.) It has been shown earlier [215] that FA leukocytes produce the enhanced amount of hydroxyl or hydroxyl-like free radicals, which are probably formed by the Fenton reaction. It was suggested that MF would be able to accelerate hydroxyl radical production by FA leukocytes. Indeed, we found that MF significantly enhanced luminol-amplified CL produced by non-stimulated and PMA-stimulated FA leukocytes but did not affect at all oxygen radical production by leukocytes from FA relatives and healthy donors (Table 21.3). It is interesting that MF did not also affect the calcium ionophore A23187-stimulated CL by FA leukocytes, indicating the absence of the calcium-mediated mechanism of MF activity, at least for FA leukocytes. 

There is no doubt that more and more agents will be developed because of their ability to hit tumor cells with a particular genetic signature. For example, recent work from Dr. Scott Kern s laboratory at Johns Hopkins University has indicated that pancreatic cancer cells with functional defects in the Fanconi anemia pathway (including BRCA-2 mutations) are... 

Ross WE, Glaubiger DL, Kohn KW (1978) Protein-associated DNA breaks in cells treated with adriamycin or elhpticine. Biochim Biophys Acta 519(l) 23-30 Rothfuss A, Grompe M (2004) Repair kinetics of genomic interstrand DNA cross-hnks evidence for DNA double-strand break-dependent activation of the Fanconi anemia/BRCA pathway. Mol Cell Biol 24(1) 123-134... 

Fanconi anemia arises from a decreased abiiity to repair interstrand DNA cross-links. 

Marsit CJ, Liu M, Nelson HH et al. Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers implications for treatment and survival. Oncogene 2004 23 1000-1004. 

Cohen, M.M., Fruchtman, C.E., Simpson, S.J. Martin. A.O. (1982) The cytogenetic response of Fanconi s anemia lymphoblastoid cell lines to various clastogens. Cytogenet. Cell Genet., 34, 230-240... 

Marx. M.P., Smith, S., Heyns, A.P van Tonder, I.Z. (1983) Fanconi s anemia a cytogenetic study on lymphocyte and bone marrow cultures utilizing l,2 3,4-diepoxybutane. Cancer Genet. Cytogenet., 9, 51-60... 

Porfirio, B., Dallapiccola, B., Mokini, V., Alimena, G. Gandini, E. (1983) Failure of diepoxybutane to enhance sister chromatid exchange levels in Fanconi s anemia patients and heterozygotes. Hum. Genet., 63, 117-120... 

One of the few valid uses remaining for anabolic androgens is temporary relief of Fanconi anemia while awaiting hemopoietic cell transplantation. However, in one case a large adenoma ruptured shortly after transplantation, with a fatal result (57). 

E. coli bacteria4S) and in cultured human cells. In Fig. 21 the survival curves are given for human fibroblasts after treatment with various cispiatin concentrations50 The curves obtained for cells of patients suffering from inherited DNA repair deficiencies, such as xeroderma pigmentosum and Fanconi s anemia, clearly indicate that these cells are more susceptible to the cytotoxic activity of cispiatin than the same type of cells obtained from normal , healthy persons. 

One problem associated with the yeast 2-hybrid system is that protein interactions that are dependent on posttranslational modifications that can occur only in mammalian cells, would not be detected. For example, monoubiquitinylation and serine phosphorylation of a Fanconi anemia complementation group D2 protein (FANC-D2) are both required for mediating cellular resistance to ionizing radiation (122), an interaction that would be missed using this approach. 

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