Muindi J F, Scher H I, Rigas J R, Warrell R P, Young C W
Developmental Chemotherapy Service, Memorial Sloan Kettering Cancer Center, New York, New York 10021.
Cancer Res. 1994 Apr 15;54(8):2125-8.
The addition of lipid hydroperoxides greatly accelerates the rate of oxidative catabolism of all-trans-retinoic acid (RA) in human cell microsomes; hydroperoxy metabolites of the arachidonate cascade are particularly active in the microsomal system. We have measured the plasma content of lipid peroxides in cancer patients during the course of therapy with RA, seeking to assess whether a correlation exists between the rate of oxidative catabolism of exogenously administered RA and whole body lipid peroxide levels. The assay used for plasma lipid peroxides is the capacity to react with thiobarbituric acid under specified conditions; the result is expressed as TBARS (thiobarbituric acid reactive substances). RA administration produced its own accelerated clearance RA within 72 h. Patients were considered to have "normal" or "rapid" baseline catabolism of RA if their Day 1 area under RA concentration over time curve was greater or less than 300 ng.h/ml, respectively. The mean plasma TBARS levels were: 12 normal volunteers = 0.14 microM; 19 "normal" RA catabolizers = 0.25 microM; and 14 "rapid" catabolizers = 0.82 microM. P = 0.008 (rapid catabolizers versus normal volunteers) and 0.05 (rapid catabolizers versus normal catabolizers). Repeat TBARS determinations were made during the course of therapy in 17 patients, all of whom converted to "rapid" RA catabolism on therapy. An increase in plasma TBARS levels > or = 20% of baseline was observed in 5 of 5 prostate cancer patients and 8 of 12 lung cancer patients treated with continuous RA therapy for 2 and 4 weeks, respectively. These observations support the hypothesis that high levels of lipid peroxides and rapid oxidative catabolism of RA are positively correlated.
脂质氢过氧化物的添加极大地加速了全反式维甲酸（RA）在人细胞微粒体中的氧化分解代谢速率；花生四烯酸级联反应的氢过氧化代谢产物在微粒体系统中特别活跃。我们测量了癌症患者在接受RA治疗过程中血浆脂质过氧化物的含量，试图评估外源性给予的RA的氧化分解代谢速率与全身脂质过氧化物水平之间是否存在相关性。用于检测血浆脂质过氧化物的方法是在特定条件下与硫代巴比妥酸反应的能力；结果以硫代巴比妥酸反应性物质（TBARS）表示。给予RA后72小时内其自身清除加速。如果第1天RA浓度随时间曲线下的面积分别大于或小于300 ng·h/ml，则患者被认为具有RA的“正常”或“快速”基线分解代谢。血浆TBARS的平均水平为：12名正常志愿者 = 0.14 μM；19名“正常”RA分解代谢者 = 0.25 μM；14名“快速”分解代谢者 = 0.82 μM。P = 0.008（快速分解代谢者与正常志愿者相比）和0.05（快速分解代谢者与正常分解代谢者相比）。在17名患者的治疗过程中进行了重复的TBARS测定，所有患者在治疗时均转变为“快速”RA分解代谢。分别接受持续RA治疗2周和4周的5例前列腺癌患者中的5例以及12例肺癌患者中的8例观察到血浆TBARS水平升高≥基线的20%。这些观察结果支持了脂质过氧化物水平高与RA快速氧化分解代谢呈正相关的假设。
