Abstract
Plasma samples were collected from 20 patients undergoing phase I clinical trial with flavone-8-acetic acid (FAA; 4.8 g m-2 per dose) in combination with recombinant human interleukin-2 (rhIL-2; 6-18 i.u. m-2 per day) for the treatment of metastatic melanoma. Samples were analysed for nitrate content as an indication of the oxidation of L-arginine to nitric oxide. Pretreatment plasma nitrate levels (53 +/- 4 microM) were significantly above those of healthy volunteers (19 +/- 4 microM). The maximum plasma nitrate concentration obtained after treatment, 190 +/- 29 microM (range 49 to 655 microM), was comparable to that of mice treated with FAA. Most of the increases occurred 3-5 days after initiation of a 5 day infusion of rhIL-2, but three of the increases occurred within 2 days of a 1 h infusion of FAA alone. The maximum plasma nitrate concentrations of the three patients which underwent remission (two complete, one partial) following treatment (368 +/- 143 microM) were significantly higher (P < 0.05) than those of patients with progressive disease. Hypotension was the major dose-limiting side effect, and there was no relationship between the degree of hypotension and the rise in plasma nitrate. The results provide evidence that treatment of patients with FAA and rhIL-2 induce the synthesis of nitric oxide, a physiological mediator and potential cytotoxic agent.
Highlights
Twenty patients with metastatic melanoma were entered into a phase I clinical trial of flavone-8acetic acid (FAA) (Lipha Lyonnaise Industrielle, Lyons, France) combined with recombinant human interleukin-2 (rhIL-2) (Proleukin, Eurocetus, Amsterdam, Netherlands)
For patients 9-20, FAA and rhIL-2 were given as described except that rIL-2 was given on days 8-12 only
For the 20 patients entered in the trial, pretreatment concentrations of nitrate in plasma prior to administration of FAA and rIL-2 were significantly higher than concentrations in plasma from healthy volunteers (P
Summary
Clinical methodsTwenty patients with metastatic melanoma were entered into a phase I clinical trial of FAA (Lipha Lyonnaise Industrielle, Lyons, France) combined with rhIL-2 (Proleukin, Eurocetus, Amsterdam, Netherlands). All patients had progressive disease and a performance status < 3 on a 5-grade scale according to WHO criteria (Miller et al, 1981). For patients 1-8, FAA (4.8 g m2) was given as a 1 h infusion in 500 ml 0.9% saline without urine alkalinisation on days 1, 8, and 15. For patients 9-20, FAA and rhIL-2 were given as described except that rIL-2 was given on days 8-12 only. Patients were assessed for clinical responses according to standard WHO criteria (Miller et al, 1981). Each patient received a second course of treatment after 2 weeks unless a complete response to treatment or evidence of disease progression was observed
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