demecolcine and Ataxia-Telangiectasia

In the continuous presence of Colcemid, the mitotic index in cultures of nine human tumor cell lines began to increase immediately upon addition of the drug. For 12 human normal (nontumorigenic) cell lines, the mitotic index did not begin to increase for some 2 to 3 h after the addition of Colcemid. The effect was independent of whether the cells were of fibroblast or epithelial origin and occurred over a 1000-fold range of Colcemid concentrations. No such differential effect was seen with single concentrations of either Taxol or nocodazole, but a similar delayed effect was seen for two concentrations of vinblastine. These observations suggest a fundamental difference between human normal and human tumor cells involving a cell cycle checkpoint in G2, about 1 to 2 h before mitosis.

Topics: Ataxia Telangiectasia; Cell Cycle; Cell Line; Demecolcine; Fibroblasts; Humans; Lymphocytes; Mitosis; Nocodazole; Paclitaxel; Time Factors; Tumor Cells, Cultured; Vinblastine

We have used a multi-parameter flow-cytometric technique to analyse changes in cell-cycle phase distribution (early and late G1, S and G2+M phases) for normal and X-ray-sensitive (ataxia-telangiectasia, A-T) lymphoblastoid cells exposed to X-irradiation and sodium butyrate (either alone or in combination). Sodium butyrate, an inhibitor of histone deacetylase, is a useful pharmacological tool for determining the proposed role of a histone acetylation-based chromatin surveillance system in controlling cell-cycle responses to DNA damage. We report that X-irradiated A-T cells (acute doses up to 1.5 Gy) demonstrate deficiencies in the capacity to traverse G1 and G2+M phases, although we can find no evidence of the specific involvement of a sodium butyrate-sensitive process in normal cells or abnormalities in the responses of A-T cells to the drug. We conclude that abnormal cellular control of G1 transition in A-T may be the basis of disturbed cellular differentiation in vivo, particularly in non-proliferating tissues under conditions of accumulated environmental or spontaneous DNA damage.

Topics: Ataxia Telangiectasia; Butyrates; Butyric Acid; Cell Cycle; Cell Division; Cell Transformation, Viral; Chromatin; Demecolcine; Deoxyribonucleases; DNA; Flow Cytometry; Herpesvirus 4, Human; Histone Deacetylase Inhibitors; Humans; Lymphocytes; Ribonucleases; RNA; Time Factors