Specific, reversible G1 arrest by UCN-01 in vivo provides cytostatic protection of normal cells against cytotoxic chemotherapy in breast cancer
Benjamin B. Mull, J. Andrew Livingston, Nalini Patel, Tuyen Bui, Kelly K. Hunt, Khandan Keyomarsi
Abstract
BACKGROUND: 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. 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. METHODS: Murine 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. RESULTS: UCN-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. CONCLUSIONS: UCN-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.