Anti-tumour activity in vitro and in vivo of selective differentiating agents containing hydroxamate
| Autor: | Michael J. Kelso, C. Hansen, Ling Qiu, David P. Fairlie, M. L. West, Peter G. Parsons |
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| Rok vydání: | 1999 |
| Předmět: |
Cancer Research
Skin Neoplasms Cell Survival Cellular differentiation Transplantation Heterologous Mice Nude Biology Hydroxamic Acids Histone H4 Mice In vivo Tumor Cells Cultured melanoma medicine Animals Humans Tumor Stem Cell Assay histone acetylation Cell Differentiation Regular Article Dendritic Cells Molecular biology In vitro Chromatin Trichostatin A Histone differentiating agents Oncology Mechanism of action Biochemistry biology.protein Drug Screening Assays Antitumor medicine.symptom medicine.drug |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/sj.bjc.6690493 |
| Popis: | A series of hydroxamates, which are not metalloprotease inhibitors, have been found to be selectively toxic to a range of transformed and human tumour cells without killing normal cells (fibroblasts, melanocytes) at the same concentrations. Within 24 h of treatment, drug action is characterized by morphological reversion of tumour cells to a more normal phenotype (dendritic morphology), and rapid and reversible acetylation of histone H4 in both tumour and normal cells. Two hydroxamates inhibited growth of xenografts of human melanoma cells in nude mice; resistance did not develop in vivo or in vitro. A third hydroxamate, trichostatin A, was active in vitro but became inactivated and had no anti-tumour activity in vivo. Development of dendritic morphology was found to be dependent upon phosphatase activity, RNA and protein synthesis. Proliferating hybrid clones of sensitive and resistant cells remained sensitive to ABHA, indicating a dominant-negative mechanism of sensitivity. Histone H4 hyperacetylation suggests that these agents act at the chromatin level. This work may lead to new drugs that are potent, and selective anti-tumour agents with low toxicity to normal cells. © 1999 Cancer Research Campaign |
| Databáze: | OpenAIRE |
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