期刊
PROSTATE CANCER AND PROSTATIC DISEASES
卷 16, 期 4, 页码 357-361出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/pcan.2013.28
关键词
disulfiram; epigenetics; demethylation; hypomethylation
资金
- NIH/NCI [CA58236]
- Commonwealth Foundation
- David H Koch Charitable Foundation
- DOD [W81XWH-09-1-0149]
- Cancer Center Core Grant [P30 CA006973]
- Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH) [P30 CA006973, UL1 RR 025005]
- Shared Instrument Grant [1S10RR026824-01]
- National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1 RR 025005]
- NIH Roadmap for Medical Research
BACKGROUND: Preclinical drug screens identified disulfiram as a potent in vitro inhibitor of prostate cancer (PCa) cell growth. Although many mechanisms for its anticancer activity have been proposed, tumor suppressor gene re-expression through promoter demethylation emerged as one of the more plausible. METHODS: We conducted an open-label, dose escalation trial of disulfiram in men with non-metastatic recurrent PCa after local therapy. Dose escalation occurred if a demethylating 'response' (that is, >= 10% decrease in peripheral blood mononuclear cell (PBMC) global 5-methyl cytosine (5(me)C) content) was observed in <3 patients in cohort 1. Cohorts 1 and 2 received disulfiram 250 mg and 500 mg daily, respectively. The primary end point was the proportion of subjects with a demethylation response. Secondary end points included the rate of PSA progression at 6 months, changes in PSA doubling time and safety/tolerability. RESULTS: Changes in global 5(me)C content were observed in two of nine patients (22.2%) in cohort 1 and 3 of 10 (30.0%) in cohort 2. Only five subjects were on trial for >= 6 months, all were in cohort 1 and all had PSA progression by 6 months. No changes in PSA kinetics were observed in either cohort. Disulfiram was poorly tolerated with six patients experiencing grade 3 adverse events (three per cohort). Three of the responders displayed pretreatment instability in their 5(me)C content. CONCLUSIONS: A minority of patients had transient global PBMC demethylation changes. Instability in 5(me)C may limit the reproducibility of these findings, limiting our ability to confirm our hypothesis. Given the toxicities and no clinical benefits, further development of disulfiram should not be pursued in this population.
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