Cisplatin Chronotherapy and Disulfiram Rescue Reduce Toxicity without Interfering with Anticancer Activity: Animal Findings and Preliminary Clinical Experiences

Reinhard V. Roemeling Department of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA

Randy Olshefski Department of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA

Todd Langevin Department of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA

John Berestka Department of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA

John J. Reusch Department of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA

Jane E.-B. Reusch Department of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA

David Lakatua Department of Pathology, University of Minnesota, Minneapolis, MN, 55455, USA

Mark R. Wick Department of Pathology, University of Minnesota, Minneapolis, MN, 55455, USA

William J. M. Hrushesky Department of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA

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Abstract

Cisplatin-induced mortality and nephrotoxicity are each predictably worse when the drug is given at certain points within the circadian schedule. Oral disulfiram protects rats from toxic effects at some circadian stages but not others. This manuever does not diminish the anticancer activity of cisplatin in these rats. Human beings given 2 g of oral disulfiram and high doses of cisplatin at the circadian stage associated with least cisplatin nephrotoxicity (prospectively determined potassium excretion acrophase) suffer little or no kidney damage. Disulfiram administration apparently does not interfere with the antineoplastic activity of cisplatin in humans. This is the first demonstration of the feasibility of assignment of treatment time according to a measure of the patient's ‘internal clock’ as assessed by pretreatment marker rhythmometry. It also establishes the feasibility of giving disulfiram to human beings.

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Cisplatin Chronotherapy and Disulfiram Rescue Reduce Toxicity without Interfering with Anticancer Activity: Animal Findings and Preliminary Clinical Experiences

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Cisplatin Chronotherapy and Disulfiram Rescue Reduce Toxicity without Interfering with Anticancer Activity: Animal Findings and Preliminary Clinical Experiences

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