Journal
BRITISH JOURNAL OF CANCER
Volume 122, Issue 6, Pages 812-822Publisher
SPRINGERNATURE
DOI: 10.1038/s41416-019-0707-z
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Funding
- National Cancer Institute of the National Institutes of Health [CA1522218, CA223772]
- Cancer Center Support Grant [P30CA016672]
- Cancer Prevention and Research Institute of Texas [RP170079, RP180712]
- Congressionally Directed Medical Research Programs [W81XWH0510255]
- Paul Calabresi Clinical Oncology Research Career Development Program [K12 CA088084]
- U.S. Department of Defense (DOD) [W81XWH0510255] Funding Source: U.S. Department of Defense (DOD)
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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.
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