PLASMA NITRATE PLUS NITRITE CHANGES DURING CONTINUOUS INTRAVENOUS-INFUSION INTERLEUKIN-2

Nitric oxide (NO), a biologically active mediator generated in many ce ll types by the enzyme NO synthase, may play an important role in card iovascular toxicity that is frequently observed in cancer patients dur ing intravenous (i.v.) interleukin 2 (IL-2) therapy. The induction of NO synthase and the production of NO seem to be involved in the pathog enesis of the vascular leakage syndrome, as well as in the regulation of myocardial contractility. In the present study, we evaluated the pa ttern of plasmatic NO changes during multiple cycles of continuous i.v . infusion (CIVI) of IL-2 in ten advanced cancer patients (five males, five females, median age 59 years, range 33-67 years; eight affected by renal cell cancer and two affected by malignant melanoma). The pati ents received IL-2 at 18 MIU m(-2) day(-1) (14 cycles) or 9 MIU m(-2) day(-1) (seven cycles) for 96 h, repeated every 3 weeks. Interferon al pha (IFN alpha) was also administered subcutaneously (s.c.) during the 3 week interval between IL-2 cycles. For each cycle, plasma samples w ere collected before treatment (t(0)), 24 h (t(1)), 48 h (t(2)), 72 h (t(3)) and 96 h (t(4)) after the start of IL-2 infusion, and 24 h afte r the end of the cycle. NO concentration was determined spectrophotome trically by measuring the accumulation of both nitrite and nitrate (af ter reduction to nitrite). The following observations may be drawn fro m data analysis: (1) plasma nitrate + nitrite significantly raised dur ing treatment (P = 0.0226 for t(0) vs t(3)), but statistical significa nce was retained only when cycles administered with IL-2 18 MIU m(-2) day(-1) are considered (P = 0.0329 for t(0) vs t(3); P = 0.0354 for t( 0) vs t(2) vs t(4)) (dose-dependent pattern); (2) during subsequent cy cles a significant trend toward a progressive increase of plasma nitra te + nitrite levels, with increasing cumulative dose of IL-2, was obse rved (linear regression coefficient r = 0.62, P = 0.0141 for t(0); r = 0.80, P = 0.0003 for t(1); r = 0.62, P = 0.013 for t(2); r = 0.69, P = 0.045 for t(3)); (3) plasma nitrate + nitrite levels peaked earlier in subsequent cycles than in the first cycle; (4) all patients experie nced hypotension. The mean of the systolic blood pressure values was s ignificantly lower at the time of plasma nitrate + nitrite peak than a t t(0) (P = 0.0004); (5) the two cases of grade III hypotension occurr ed in patients with the higher mean and peak plasma nitrate + nitrite values. We conclude that determination of plasma nitrate + nitrite lev els during CIVI IL-2 can usefully estimate, in a dose-dependent patter n, the degree of peripheral vascular relaxation and capillary leakage associated with cytokine action, clinically manifested as hypotension. However, isolated cardiac toxicity that continues to represent a rele vant problem during IL-2 therapy, does not appear to correlate with pl asma nitrate + nitrite levels; therefore, further studies are required to understand adequately the mechanisms underlying IL-2 induced cardi ac toxicity.