J. Kovach, M. Ames, G. Powis
Nov 1, 1979
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Influential Citations
42
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Quality indicators
Journal
Cancer research
Abstract
Abstract Indicine N-oxide (NSC 132319), the first pyrrolizidine alkaloid to be studied as an antitumor agent in humans, was administered to 29 patients with advanced cancer by 10-min infusion daily for five consecutive days in planned escalations ranging from a daily dose of 0.15 to 3.0 g/sq m. At all doses tested, plasma concentrations of indicine N-oxide exhibited a biphasic decline best approximated by a two-compartment open model. At daily doses up to 1.5 g/sq m, the distributive and postdistributive half-lives of plasma elimination ranged from 0.8 to 3.7 min and from 90.6 to 171.7 min, respectively. Total body clearance ranged from 3.6 to 6.2 ml/min/kg. At the highest dose tested, 3 g/sq m, a striking, and as yet unexplained, increase in the half-life of the initial distribution phase and a decrease in total body clearance were noted. Approximately 40% of the administered dose of indicine N-oxide was eliminated in the urine within 24 hr as unmetabolized drug and 2% as the free base indicine. Dose-limiting toxicity of the drug was reversible leukopenia and/or thrombocytopenia. Repetitive courses of indicine N-oxide had a cumulative effect on the severity of myelosuppression, and prior treatment with a nitrosourea enhanced the hemopoietic toxicity of indicine N-oxide. Other toxicities included mild nausea and vomiting during treatment, reversible increases (≥20% of pretreatment values) in serum creatinine in 11 of 43 courses, and transient alterations in serum glutamic-oxaloacetic transaminase. No objective responses were noted, but five patients with advanced gastrointestinal cancer had stability of disease for at least four months. For subsequent studies of drug activity in patients with solid tumors, we would recommend 3.0 g/sq m daily for five days repeated every five weeks. Indicine N-oxide should be used with great caution, or not at all, in patients treated previously with nitrosoureas or other drugs known to produce cumulative bone marrow toxicity.