Plasma nitrate plus nitrite changes during continuous intravenous infusion interleukin 2.
Plasma nitrate plus nitrite changes during continuous intravenous infusion interleukin 2.
复制标题
连续静脉输注白细胞介素2期间的血浆硝酸盐和亚硝酸盐的变化。
DOI：
10.1038/bjc.1996.533
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发表时间：
1996-10
影响因子：
8.8
通讯作者：
Rugarli, C
中科院分区：
文献类型：
--
作者：
Citterio, G;Pellegatta, F;DiLucca, G;Fragasso, G;Scaglietti, U;Pini, D;Fortis, C;Tresoldi, M;Rugarli, C
一氧化氮（NO）是一种在许多细胞类型中由NO合酶产生的生物活性介质，可能在癌症患者静脉内（i. v.）白细胞介素2（IL-2）治疗。NO合成酶的诱导和NO的产生似乎参与了血管渗漏综合征的发病机制，以及在心肌收缩力的调节。在本研究中，我们评估了10名晚期癌症患者（5名男性，5名女性，中位年龄59岁，范围33-67岁; 8名受肾细胞癌影响，2名受恶性黑色素瘤影响）连续静脉输注（CIVI）IL-2多个周期期间血浆NO变化的模式。患者接受18 MIU m-2 day-1（14个周期）或9 MIU m-2 day-1（7个周期）的IL-2治疗96 h，每3周重复一次。在IL-2周期之间的3周间隔期间，还皮下（s.c.）给予干扰素α（IFN α）。对于每个周期，在治疗前（t0）、IL-2输注开始后24 h（t1）、48 h（t2）、72 h（t3）和96 h（t4）以及周期结束后24 h采集血浆样本。通过测量亚硝酸盐和硝酸盐（还原成亚硝酸盐后）的积累，用比色法测定NO浓度。结果表明：（1）血浆硝酸盐+亚硝酸盐浓度在处理期间显著升高（t0 vs t3的P = 0.0226），但仅当考虑IL-2 18 MIU m-2 day-1给药周期时，才保持统计学显著性（t0 vs t3，P = 0.0329; t0 vs t2 vs t4，P = 0.0354）（剂量依赖性模式）;（2）在随后的周期中，观察到血浆硝酸盐+亚硝酸盐水平随着IL-2累积剂量的增加而显著增加的趋势（线性回归系数r = 0.62，P = 0.0141，t0; r = 0.80，P = 0.0003，t1; r = 0.62，P = 0.013，t2; r = 0.69，P = 0.045，t3）;（3）血浆硝酸盐+亚硝酸盐水平在随后的周期中比第一周期更早达到峰值;（4）所有患者都发生了低血压。血浆硝酸盐+亚硝酸盐峰值时收缩压均值明显低于t0时（P = 0.0004）;（5）2例III级低血压患者均发生在血浆硝酸盐+亚硝酸盐峰值和均值较高的患者。我们得出结论，血浆硝酸盐+亚硝酸盐水平的测定在CIVI IL-2可以有效地估计，在剂量依赖性模式，外周血管舒张和毛细血管渗漏的程度与细胞因子的作用，临床表现为低血压。然而，孤立的心脏毒性，继续代表IL-2治疗期间的相关问题，似乎不与血浆硝酸盐+亚硝酸盐水平;因此，需要进一步的研究，充分了解IL-2诱导的心脏毒性的机制。
Nitric oxide (NO), a biologically active mediator generated in many cell types by the enzyme NO synthase, may play an important role in cardiovascular toxicity that is frequently observed in cancer patients during intravenous (i.v.) interleukin 2 (IL-2) therapy. The induction of NO synthase and the production of NO seem to be involved in the pathogenesis of the vascular leakage syndrome, as well as in the regulation of myocardial contractility. In the present study, we evaluated the pattern 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 patients 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 alpha (IFN alpha) was also administered subcutaneously (s.c) during the 3 week interval between IL-2 cycles. For each cycle, plasma samples were collected before treatment (t0), 24 h (t1), 48 h (t2), 72 h (t3) and 96 h (t4) after the start of IL-2 infusion, and 24 h after the end of the cycle. NO concentration was determined spectrophotometrically by measuring the accumulation of both nitrite and nitrate (after reduction to nitrite). The following observations may be drawn from data analysis: (1) plasma nitrate + nitrite significantly raised during treatment (P = 0.0226 for t0 vs t3), but statistical significance was retained only when cycles administered with IL-2 18 MIU m-2 day-1 are considered (P = 0.0329 for t0 vs t3; P = 0.0354 for t0 vs t2 vs t4) (dose-dependent pattern); (2) during subsequent cycles a significant trend toward a progressive increase of plasma nitrate + nitrite levels, with increasing cumulative dose of IL-2, was observed (linear regression coefficient r = 0.62, P = 0.0141 for t0; r = 0.80, P = 0.0003 for t1; r = 0.62, P = 0.013 for t2; r = 0.69, P = 0.045 for t3); (3) plasma nitrate + nitrite levels peaked earlier in subsequent cycles than in the first cycle; (4) all patients experienced hypotension. The mean of the systolic blood pressure values was significantly lower at the time of plasma nitrate + nitrite peak than at t0 (P = 0.0004); (5) the two cases of grade III hypotension occurred in patients with the higher mean and peak plasma nitrate + nitrite values. We conclude that determination of plasma nitrate + nitrite levels during CIVI IL-2 can usefully estimate, in a dose-dependent pattern, 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 relevant problem during IL-2 therapy, does not appear to correlate with plasma nitrate + nitrite levels; therefore, further studies are required to understand adequately the mechanisms underlying IL-2-induced cardiac toxicity.
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影响因子：
2.9
作者：
GREEN, LC;WAGNER, DA;TANNENBAUM, SR
通讯作者：
TANNENBAUM, SR
影响因子：
37.8
作者：
PAULUS, WJ;VANTRIMPONT, PJ;SHAH, AM
通讯作者：
SHAH, AM
影响因子：
10.8
作者：
PETROS, A;LAMB, G;VALLANCE, P
通讯作者：
VALLANCE, P
影响因子：
8.8
作者：
KILBOURN, RG;FONSECA, GA;LOGOTHETIS, CJ
通讯作者：
LOGOTHETIS, CJ
影响因子：
8.8
作者：
MEYER, J;LENTZ, CW;TRABER, DL
通讯作者：
TRABER, DL