Biomedical subjects

C Rössig

Publications and source records attributed to C Rössig.

4 recordsLinked to original sources

PubMed2001

Modulation of ara-CTP levels by fludarabine and hydroxyurea in leukemic cells.

The rate of ara-cytosine triphosphate (ara-CTP) accumulation and its retention has been correlated with 1-beta-D-arabinofuranosylcytosine (ara-C)-mediated toxicity and clinical outcome in childhood and adult leukemia. We tested to what extent preincubation with the ribonucleotide reductase inhibitors fludarabine (F-ara-A) and hydroxyurea (HU) enhanced ara-CTP levels in two human myeloid (HL-60, CMK) and two lymphoblastic leukemia cell lines (MOLT-4, BLIN-1) and also in blasts from 28 children with acute leukemia (AML: 14, ALL: 14). Incubation experiments carried out with cell lines showed F-ara-A and HU to be equipotent in increasing ara-CTP levels. The highest increase was observed in HL-60 cells whereas preincubation had no modulatory effect in MOLT-4 cells. Accordingly, modulation of intracellular ara-CTP levels differed between the subtypes of childhood acute leukemia: whereas in T-ALL (five) preincubation with F-ara-A and HU had no effect on intracellular ara-C metabolism, increased ara-CTP levels were seen in some cases of pre-B-ALL (seven). In myelogenous blasts (12) clinically relevant enhancement of ara-C toxification was regularly obtained with both, F-ara-A (1.9-fold) and HU (1.5-fold). In conclusion, our data suggest that combinations of ara-C and ribonucleotide reductase inhibitors are apt to increase ara-CTP levels depending on the individual cell type and its sensitivity towards ara-C modulators.

Adult↗

PubMed1999

All-trans-retinoic acid increases cytosine arabinoside cytotoxicity in HL-60 human leukemia cells in spite of decreased cellular ara-CTP accumulation.

BACKGROUND: Accumulation of the cytosine arabinoside (ara-C) metabolite ara-C-triphosphate (ara-CTP) in leukemic blast cells is considered to be the main determinant of ara-C cytotoxicity in vitro and in vivo. Retinoids such as all-trans-retinoic acid (ATRA) have been shown to increase the sensitivity of acute myelogenous leukemic (AML) blast cells to ara-C. To investigate the mechanism of this sensitisation, the hypothesis was tested that ATRA augments cellular ara-CTP levels in human-derived myelogenous leukemia HL-60 cells. MATERIALS AND METHODS: The effect of ATRA and 13-cis-retinoic acid on ara-CTP accumulation and ara-C-induced apoptosis was studied. Ara-CTP levels were measured by high-performance liquid chromatography (HPLC), cytotoxicity by the tetrazolium (MTT) assay, and apoptosis by occurrence of DNA fragmentation (gel electrophoresis), cell shrinkage and DNA loss (flow cytometry). RESULTS: Pretreatment of HL-60 cells with ATRA (0.01-1 microM) caused a significant decrease in intracellular ara-CTP levels; e.g., incubation for 72 hours with ATRA 1 microM prior to one hour ara-C 10 microM reduced ara-CTP levels to 41% +/- 4% of control. Similar results were obtained after preincubation with 13-cis-retinoic acid. In spite of decreased ara-CTP levels, the cytotoxicity of the combination was supraadditive and ATRA augmented ara-C-induced apoptosis. CONCLUSION: At therapeutically relevant concentrations ATRA increased ara-C cytotoxicity and ara-C induced apoptosis but this augmentation is not the corollary of elevated ara-CTP levels. The feasibility of ara-C treatment optimisation via strategies other than those involving elevation of ara-CTP levels should be investigated further.

Analysis of Variance↗

PubMed1994

Audiologic manifestations in fetal alcohol syndrome assessed by brainstem auditory-evoked potentials.

In 29 of 36 children with fetal alcohol syndrome brainstem auditory-evoked potentials were performed and the auditory threshold was determined. The hearing of patients with a pathologic finding was then subject to a thorough ear-nose-throat examination. Additionally the IQ was determined and an audiolinguistic examination was carried out. Seventy-five % of the children showed a peripheral hearing disorder on the basis of conductive hearing loss. In two children (7%) sensorineural hearing loss was located to the inner ear. A dysfunction of the auditory pathway was found in 6 patients (21%). The results of an isolated ear-nose-throat examination in 7 further children supported these findings. The mean performances in the linguistic tests were far below average and displayed a strong relation to the IQ. This study shows that a peripheral hearing disorder, especially an obstruction of the auditory tube as well as dysfunctions of the inner ear and the central hearing pathway, are different manifestations of the fetal alcohol syndrome. An etiologic connection between craniofacial abnormalities in these children and an increased susceptibility to peripheral hearing disorders could not be demonstrated. To avoid a retardation of the linguistic development in addition to the intellectual deficits a strong emphasis must be put on an early and comprehensive auditory examination of children with FAS.

Adolescent↗

PubMedDate not supplied

Adoptive cellular immunotherapy with CD19-specific T cells.

BACKGROUND: No effective therapeutic modalities exist for the treatment of relapsed high risk acute lymphoblastic leukemia (ALL). Adoptive cellular immunotherapy by transfusion of polyclonal donor lymphocytes is not always effective and is limited by cellular cross-reactivity with normal tissues, leading to development of clinical graft-versus-host disease (GVHD). METHOD: To develop an immunotherapeutic strategy for targeted elimination of residual leukemic blasts, human T cells were gene-modified to express CD19-specific chimeric receptors. RESULTS: Gene-modified T cells specifically lyse CD19-expressing lymphatic blast cells, however, they show a limited proliferative response to stimulation with CD19. Integration of the signal transduction domain of the costimulatory molecule CD28 enhances the proliferative properties of the gene-modified T cells. CONCLUSIONS: Adoptive transfer of gene-modified virus-specific T cells may provide a useful strategy for prevention and early treatment of ALL relapses following allogeneic stem cell transplantation.

Antigens, CD19↗