Phase I clinical and pharmacokinetic study of diethyldithiocarbamate as a chemoprotector from toxic effects of cisplatin.
Diethyldithiocarbamate (DDTC) has been shown to provide protection against most clinically significant toxic effects from cisplatin (DDP) without inhibiting tumor response in a variety of murine animal models. We conducted a phase I clinical and pharmacokinetic study of DDTC in combination with DDP to establish the types and severity of toxic effects and to determine whether protection of normal tissues and tumors occurs. Twenty-two courses of DDP plus DDTC were given to 10 patients. No nephrotoxic effects were seen at DDP doses of 50-120 mg/m2, and three patients had amelioration of nausea and vomiting. Objective antitumor responses were observed. Dose-limiting toxic effects from DDTC occurred at 150 mg/kg; these consisted of numbness in the infusion arm often accompanied by severe diaphoresis, chest discomfort, and agitation during DDTC infusion. These toxic effects resolved spontaneously, however, after termination of the infusion. The preliminary results suggest that plasma levels of DDTC that provide excellent protection in rodents were exceeded at the doses used in our clinical study without compromising antitumor response.
Qazi
R
R
Medical Oncology Unit, University of Rochester, NY.
Chang
A Y
AY
Borch
R F
RF
Montine
T
T
Dedon
P
P
Loughner
J
J
Bennett
J M
JM
D002945:Cisplatin / Q000633:toxicity*; D004050:Ditiocarb / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004341:Drug Evaluation; D006801:Humans; D007668:Kidney / Q000187:drug effects
D004050:Ditiocarb; D002945:Cisplatin