Abstract
BackgroundLow-dose UCN-01 mediates G1 arrest in normal proliferating cell lines with an intact G1 to S transition but not tumour cells with a deregulated G1 to S checkpoint. Here we hypothesised that UCN-01 is effective in mediating a selective, reversible G1 arrest of normal proliferating cells, resulting in decreased chemotoxicity, improved tolerance and enhanced chemotherapeutic efficacy in vivo in both non-tumour-bearing mice and in breast cancer cell line xenograft models.MethodsMurine small bowel epithelium was used to examine the kinetics and mechanism of low-dose UCN-01-mediated arrest of normal proliferating cells and if it can protect tumour-bearing mice (MDA-MB-468 xenografts) against the toxic effects of chemotherapy (5-fluorouricil (5-FU)) allowing for its full therapeutic activity.ResultsUCN-01 causes significant, reversible arrest of normal gut epithelial cells at 24 h; this arrest persists for up to 7 days. Normal cellular proliferation returns by 2 weeks. Pre-treatment of both non-tumour-bearing and MDA-MB-468 tumour-bearing mice with UCN-01 prior to bolus 5-FU (450 mg/kg) yielded enhanced therapeutic efficacy with significantly decreased tumour volumes and increased survival.ConclusionsUCN-01 mediates a specific, reversible G1 arrest of normal cells in vivo and provides a cytoprotective strategy that decreases toxicity of cytotoxic chemotherapy without compromising efficacy.
Highlights
Low-dose UCN-01 mediates G1 arrest in normal proliferating cell lines with an intact G1 to S transition but not tumour cells with a deregulated G1 to S checkpoint
Using a mouse small bowel epithelium model system, we evaluated various dosing strategies to optimise the efficacy of UCN-01 as a cytoprotective agent and characterised the molecular changes associated with cell cycle arrest of normal cells in vivo
UCN-01 reversibly arrests normal gut epithelium in G1 To demonstrate the ability of UCN-01 to arrest normally dividing cells in vivo, we examined the epithelium of the small intestine of nu/nu nude mice
Summary
Low-dose UCN-01 mediates G1 arrest in normal proliferating cell lines with an intact G1 to S transition but not tumour cells with a deregulated G1 to S checkpoint. We hypothesised that UCN-01 is effective in mediating a selective, reversible G1 arrest of normal proliferating cells, resulting in decreased chemotoxicity, improved tolerance and enhanced chemotherapeutic efficacy in vivo in both non-tumour-bearing mice and in breast cancer cell line xenograft models. Strategies that can exploit the differential regulation of normal cells as compared with tumour cells to protect normal cells from chemotoxicity may allow for dose escalation, enhance the therapeutic window for currently available cytotoxic chemotherapies, and reduce the development of resistance.[1,2] To be effective, these cytoprotective strategies[3] must fulfil two major criteria: (1) cell cycle arrest must be specific to normal proliferating cells without affecting tumour cells, and (2) this arrest of normal cells must be reversible. Tumour cells, which were unresponsive to the protective agent, continue to proliferate and undergo chemotherapy-mediated cell death
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