Hydroxyurea induces chromosomal damage in G2 and enhances the clastogenic effect of mitomycin C in Fanconi anemia cells

2015 ◽  
Vol 56 (5) ◽  
pp. 457-467 ◽  
Author(s):  
Bertha Molina ◽  
Francesco Marchetti ◽  
Laura Gómez ◽  
Sandra Ramos ◽  
Leda Torres ◽  
...  
Keyword(s):  
Mitomycin C ◽  
Fanconi Anemia ◽  
Chromosomal Damage ◽  
Clastogenic Effect

Aplastic Anemia and Fanconi Anemia: Response of Lymphocytes to X-Rays and Mitomycin C

1989 ◽  
pp. 100-104 ◽  
Author(s):  
A. T. Natarajan ◽  
J. M. J. J. Vossen ◽  
M. H. van Weel-Sipman
Keyword(s):  
Aplastic Anemia ◽  
Mitomycin C ◽  
Fanconi Anemia ◽  
X Rays

Phenotypic correction of Fanconi anemia group C knockout mice

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 700-704 ◽  
Author(s):  
Kimberly A. Gush ◽  
Kai-Ling Fu ◽  
Markus Grompe ◽  
Christopher E. Walsh
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Mitomycin C ◽  
Fanconi Anemia ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Genetic Disorder ◽  
Hematopoietic Stem ◽  
Marrow Cells

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure, congenital anomalies, and a predisposition to malignancy. FA cells demonstrate hypersensitivity to DNA cross-linking agents, such as mitomycin C (MMC). Mice with a targeted disruption of the FANCC gene (fancc −/− nullizygous mice) exhibit many of the characteristic features of FA and provide a valuable tool for testing novel therapeutic strategies. We have exploited the inherent hypersensitivity offancc −/− hematopoietic cells to assay for phenotypic correction following transfer of the FANCC complementary DNA (cDNA) into bone marrow cells. Murine fancc −/− bone marrow cells were transduced with the use of retrovirus carrying the humanfancc cDNA and injected into lethally irradiated recipients. Mitomycin C (MMC) dosing, known to induce pancytopenia, was used to challenge the transplanted animals. Phenotypic correction was determined by assessment of peripheral blood counts. Mice that received cells transduced with virus carrying the wild-type gene maintained normal blood counts following MMC administration. All nullizygous control animals receiving MMC exhibited pancytopenia shortly before death. Clonogenic assay and polymerase chain reaction analysis confirmed gene transfer of progenitor cells. These results indicate that selective pressure promotes in vivo enrichment offancc-transduced hematopoietic stem/progenitor cells. In addition, MMC resistance coupled with detection of the transgene in secondary recipients suggests transduction and phenotypic correction of long-term repopulating stem cells.

Abstract A99: Phase I trial of veliparib or mitomycin C + veliparib in pts with Fanconi anemia pathway (FA) repair defects.

2011 ◽  
Author(s):  
Miguel A. Villalona-Calero ◽  
Wenrui Duan ◽  
Weiqiang Zhao ◽  
Li Gao ◽  
Jennifer Thurmond ◽  
...  
Keyword(s):  
Phase I ◽  
Mitomycin C ◽  
Fanconi Anemia ◽  
Phase I Trial ◽  
Fanconi Anemia Pathway

Protein Replacement by Receptor-Mediated Endocytosis Corrects the Sensitivity of Fanconi Anemia Group C Cells to Mitomycin C

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 363-369 ◽  
Author(s):  
Hagop Youssoufian ◽  
Frank A.E. Kruyt ◽  
Xiaotong Li
Keyword(s):  
Mitomycin C ◽  
Fanconi Anemia ◽  
Hematopoietic Cells ◽  
Chimeric Protein ◽  
Direct Gene Transfer ◽  
C Cells ◽  
Receptor Mediated Endocytosis ◽  
Culture Model ◽  
Complementation Groups ◽  
Anemia Group

Abstract Current methods for direct gene transfer into hematopoietic cells are inefficient. Here we show that functional complementation of Fanconi anemia (FA) group C cells by protein replacement can be as efficacious as by transfection with wild-type FAC cDNA. We expressed a chimeric protein (called His-ILFAC) consisting of the mature coding portion of gibbon interleukin-3 (IL-3) and full-length FAC inEscherichia coli. The purified bacterial protein is internalized by hematopoietic cells via IL-3 receptors. The intracellular half-life of His-ILFAC is approximately 60 minutes, which is comparable to that of the transgene-encoded FAC protein. In this cell-culture model His-ILFAC completely corrects the sensitivity of FA group C cells to mitomycin C, but it has no effect on FA cells that belong to complementation groups A and B. We suggest that receptor-mediated endocytosis of cytokine-fusion proteins may be of general use to deliver macromolecules into hematopoietic progenitor cells.

Inhibition of clastogenic effect of cyclophosphamide and mitomycin C by Neem leaf-extract in mice

1998 ◽  
Vol 12 (6) ◽  
pp. 409-412 ◽  
Author(s):  
Madhumita J. Mukhopadhyay ◽  
Anita Mukherjee
Keyword(s):  
Mitomycin C ◽  
Leaf Extract ◽  
Clastogenic Effect ◽  
Neem Leaf Extract

Developmental Programming of Bone Marrow Failure in a Murine Model of Fanconi Anemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1334-1334
Author(s):  
Ashley N. Kamimae-Lanning ◽  
Tae H. Ha ◽  
Amy M. Skinner ◽  
Thomas B. Russell ◽  
Peter Kurre
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Stem Cell ◽  
Mitomycin C ◽  
Fanconi Anemia ◽  
Murine Model ◽  
Fetal Liver ◽  
Bone Marrow Failure ◽  
Bone Marrow Progenitor ◽  
And Function

Abstract Abstract 1334 Bone marrow failure is the most common cause of morbidity and mortality from Fanconi anemia (FA), a recessively inherited disorder resulting from mutations in one of 15 known genes that cooperate in a DNA repair pathway. The underlying etiology is thought to reflect an accelerated postnatal exhaustion of the hematopoietic stem and progenitor cell (HSPC) pool. However, laboratory evidence of compromised hematopoietic function in patients generally precedes symptoms of cytopenia, and several other mesodermal-derived organ systems show defects with prenatal onset, including the skeletal system, heart, kidneys, and others. Further, recent experimental evidence in human embryonic stem cell lines suggested that RNA interference-mediated knock-down of FANCD2 and FANCA impairs development of hematopoietic cells. The fetal liver provides a unique microenvironment for development of definitive hematopoietic function and serves as a site of massive HSPC expansion. However, neither the potential developmental onset of bone marrow failure or non-stem cell-autonomous contributions in FA have been systematically clarified to-date. We relied on a murine model of FA with a transgenic disruption of Fancc to test the hypothesis that hematopoietic failure for this disease may have developmental origins. Although spontaneous bone marrow failure does not occur in this FA mouse model, animals recapitulate impaired repopulating ability, characteristic cell cycle abnormalities, and impaired cytokine responses. To determine whether number and function of fetal liver (FL) HSPCs affect postnatal hematopoietic function in FA mice, we plated unfractionated cells from 14.5 days post coitum (dpc) FL in methylcellulose and undertook a chronologic assessment of postnatal bone marrow progenitor clonogenicity. These studies showed that, compared with wild-type (wt) littermates, Fancc−/− animals demonstrate a progressive deficiency in progenitor number and function that increases with age, suggesting that HSPC attrition is developmentally programmed. Fancc−/−fetal mice revealed a 10% reduction in body mass and 33% lower total liver cell count compared with wt littermates. Cytogenetic analysis shows Fancc−/−FL cells exhibit mitomycin-c hypersensitivity characteristic of FA, with increased chromosomal breakage and radial formation. Livers of 14.5±.5 dpc Fancc−/−fetuses contain approximately 43% fewer c-Kit+Sca-1+ progenitor-enriched cells, compared with wt littermates. Cell cycle status of fetal livers revealed a characteristically increased proportion of Fancc−/− fetal liver progenitor-enriched (c-Kit+ Sca-1+) cells in G2-M phase of cell cycle, compared to wt littermate liver. When plated in methylcellulose assays, Fancc−/−FL showed an approximately 20% reduction in progenitor frequency, compared to wt littermates, and plating in mitomycin-c resulted in outgrowth of fewer colonies. Further, studies to determine the relative in vivo repopulating cell frequency were performed using CD45-isotype mismatched, submyeloablatively irradiated (750 cGy) animals. Recipients receiving unfractionated 14.5±.5 dpc Fancc−/−liver cells showed a slight, but consistent reduction in peripheral blood chimerism at serial timepoints (1–5 months) and bone marrow chimerism at sacrifice. We also found a 21% reduction in total Fancc−/−clonogenic bone marrow progenitor frequency by methylcellulose assay in primary recipients, compared to wt-transplanted controls. In sum, these studies suggest a developmental origin of hematopoietic failure in FA, whereby the prenatal onset potentially contributes to disease progression. Results contrast with a conventional model of postnatal stem cell attrition and may impact the development of preemptive therapies for FA patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals International Fanconi Anemia Registry: relation of clinical symptoms to diepoxybutane sensitivity

Blood ◽  
1989 ◽  
Vol 73 (2) ◽  
pp. 391-396
Author(s):  
AD Auerbach ◽  
A Rogatko ◽  
TM Schroeder-Kurth
Keyword(s):  
Fanconi Anemia ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
Chromosomal Breakage ◽  
Scoring Method ◽  
Cellular Sensitivity ◽  
Progressive Pancytopenia ◽  
Clastogenic Effect ◽  
Blood Specimens ◽  
Stepwise Multivariate Logistic Regression

Fanconi anemia (FA) is characterized clinically by a progressive pancytopenia, diverse congenital abnormalities and increased predisposition to malignancy. Although a variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, study of cellular sensitivity to the clastogenic effect of DNA cross-linking agents such as diepoxybutane (DEB) has been used to facilitate the diagnosis. Data from DEB-induced chromosomal breakage studies of 328 peripheral blood specimens from patients considered at risk for FA were analyzed using a stepwise multivariate logistic regression, in order to determine which method of representing the data best discriminated between DEB-sensitive (DEB+) and DEB-insensitive (DEB-) cases. Similar methods were applied to the data from the International Fanconi Anemia Registry (IFAR) to determine whether DEB+ and DEB- cases may be considered as distinct clinical entities, and if so, which variables provide the best discrimination between the two groups. We conclude that hypersensitivity to the clastogenic effect of DEB is a useful discriminator for FA. A simplified scoring method for classifying patients on the basis of eight clinical manifestations that are the best predictors for FA is presented. Our data indicate that the clinical diversity in FA is more widespread than previously recognized.

scholarly journals Reduced recruitment of 53BP1 during interstrand crosslink repair is associated with genetically inherited attenuation of mitomycin C sensitivity in a family with Fanconi anemia

Oncotarget ◽  
2017 ◽  
Vol 9 (3) ◽  
pp. 3779-3793
Author(s):  
Emilie Lesport ◽  
Alina Ferster ◽  
Armand Biver ◽  
Benoit Roch ◽  
Nadia Vasquez ◽  
...  
Keyword(s):  
Mitomycin C ◽  
Fanconi Anemia ◽  
Interstrand Crosslink ◽  
Interstrand Crosslink Repair ◽  
Crosslink Repair

Mitomycin C Test for Diagnostic Differentiation of Idiopathic Aplastic Anemia and Fanconi Anemia

PEDIATRICS ◽  
1981 ◽  
Vol 67 (1) ◽  
pp. 119-127 ◽  
Author(s):  
Jaroslav Cervenka ◽  
Diane Arthur ◽  
Carmen Yasis
Keyword(s):  
Aplastic Anemia ◽  
Mitomycin C ◽  
Fanconi Anemia ◽  
Stress Test ◽  
Fold Increase ◽  
Chromosomal Breaks ◽  
Lethal Complications ◽  
Healthy Control ◽  
Increased Sensitivity ◽  
Diagnostic Differentiation

A cytogenetic test was developed to enable the diagnostic differentiation between Fanconi anemia and the group of disorders classified as "idiopathic" aplastic anemia. The method is based on the effect of the bifunctional alkylating agent mitomycin C (MMC) on chromosomes of peripheral lymphocytes in culture 92 to 96 hours. At the highest concentration of 80 ng/ml of MMC, about a 50-fold increase of chromosomal breaks and a 200-fold increase of radial figures was observed in Fanconi anemia lymphocytes in comparison with the average values for aplastic anemia cells or cells of healthy control subjects. In addition, sister chromatid exchange analysis of cells treated with MMC demonstrated a marked inhibition of mitotic activity of lymphocytes of patients with increased sensitivity to MMC. It is advocated that the MMC-stress test should be used in each case of pancytopenia, as part of the therapy planning. The cytoreduction regimens used prior to bone marrow transplantation may produce lethal complications in patients with high clastogenic response to MMC.

Mitomycin C–Induced DNA Damage in Fanconi Anemia: Cross-Linking or Redox-Mediated Effects?

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 1116-1118 ◽  
Author(s):  
Giovanni Pagano ◽  
Adriana Zatterale ◽  
Ludmila G, Korkina
Keyword(s):  
Dna Damage ◽  
Mitomycin C ◽  
Fanconi Anemia ◽  
Cross Linking ◽  
Mediated Effects
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