Selected Aspects of Cisplatin Nephrotoxicity in the Rat and Man
Selected Aspects of Cisplatin Nephrotoxicity in the Rat and Man
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顺铂对大鼠和人的肾毒性的选定方面
DOI：
10.1007/978-1-4613-2837-7_15
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发表时间：
1984
影响因子：
2.9
通讯作者：
W. Hrushesky
中科院分区：
文献类型：
--
作者：
W. Hrushesky
胃肠道毒性、肾毒性、周围神经病变和进行性贫血都是大剂量间歇顺铂治疗的副作用。我们在临床研究中心对约 100 名接受 5 至 10 个月疗程的患者进行了特征分析。我们试图定义其中一些的分子基础，并开始使用生成的信息来设计和测试减轻这些毒性的方法。对大鼠的研究首先确定了顺铂药理学和肾毒性的昼夜节律阶段依赖性。此后的临床研究表明，与晚上相比，早上给药时尿顺铂浓度要高得多。通过在一天中与个体每日钾排泄最高的时间（通常在下午晚些时候）给药，可以很大程度上避免顺铂的肾毒性。肾毒性数据的多变量分析进一步显示，老年患者对顺铂治疗的耐受性与年轻患者一样好，甚至更好。此外，在 14 名单肾患者中，顺铂的肾毒性仅为其三分之一。胃肠道毒性的程度在某种程度上还取决于一天中的给药时间。顺铂的神经毒性通过系列分级临床检查、肌电图和神经传导研究以及腓肠神经活检的光和肌电图研究来定义和定量。这种毒性是一种不可逆的主要是感觉周围神经病。尽管顺铂在体外与 B12 强烈结合，但我们没有发现任何证据表明 B12 可以阻断丙二酸转化为丙二酰 COA 或同型半胱氨酸转化为蛋氨酸（每种物质都是产生脂肪酸和髓磷脂所必需的）。 B12 疗法似乎并不能预防这种毒性。顺铂引起的贫血是正常色素性和正细胞性的。血清B12、B12结合力、血清和红细胞叶酸正常。绝对没有溶血的证据。网织红细胞计数低，骨髓检查发现红细胞前体普遍减少。血清铁浓度、总铁结合力、转铁蛋白和铁蛋白均相当高。肝脏和骨髓显示铁储存增加。考虑到观察到的贫血程度，促红细胞生成素值远低于预期。这些数据表明铁的利用受到干扰。还研究了顺铂对血红素和珠蛋白合成以及铁螯合酶活性的影响。对患有 L1210 白血病的小鼠进行双硫仑治疗可降低顺铂的致死毒性并增强抗肿瘤作用。还在患者中研究了双硫仑救援对顺铂药代动力学和毒性的影响，取得了令人鼓舞的结果。各种顺铂毒性的选择性化学和时间修饰可以作为操纵其他有毒但活性药物的治疗指数的模型。
Gastrointestinal toxi city, nephrotoxicity, peripheral neuropathy, and progressive anemia are each side effects of high-dose intermittent cisplatin therapy. We have characterized each of these toxicities in a Clinical Research Center setting in about 100 patients, who received 5 to 10 monthly courses of therapy. We have attempted to define the molecular bases for some of them and have begun to use the information generated to design and test methods of lessening these toxicities. Studies in rats first defined the circadian stage dependence of cisplatin pharmacology and nephrotoxicity. Clinical studies have since documented much higher urinary cisplatin concentrations when the drug is given in the morning as compared to the evening. Cisplatin nephrotoxicity can be largely avoided by administering the drug at the time of day associated with highest daily potassium excretion for that individual (usually in the late afternoon). A multivariate analysis of kidney toxicity data further revealed that older patients tolerated cisplatin therapy as well as, or better than, their younger counterparts. Additionally, cisplatin nephrotoxicity was only one-third as great in a subset of 14 patients with a single kidney. The amount of gastrointestinal toxicity also depends to some extent upon what time of day the drug is given. The neurotoxicity of cisplatin was defined and quantitated by serial graded clinical examinations, EMG and nerve conduction studies, and light and EMG studies of sural nerve biopsies. This toxicity is an irreversible predominantly sensory peripheral neuropathy. Although cisplatin binds avidly to B12 in vitro, we find no evidence for blockage of the B12-dependent conversion of malonic acid to malonyl COA or homocysteine to methionine (each necessary for the production of fatty acids and myelin). B12 therapy does not seem to prevent this toxicity. Cisplatin-induced anemia is normochromic and normocytic. Serum B12, B12 binding capacity, serum and red cell folates are normal. There was absolutely no evidence for hemolysis. Reticulocyte counts were low, and the bone marrow examination revealed that red cell precursors were generally decreased. Serum iron concentration, total iron binding capacity, transferrin, and ferritin were each quite high. Liver and bone marrow showed increased iron stores. Erythropoietin values were much lower than they would be expected to be, given the degree of anemia observed. These data point to an interference with iron utilization. Cisplatin effects upon heme and globin synthesis and ferrochetolase activity were also studied. Disulfiram therapy in mice bearing L1210 leukemia decreases cisplatin lethal toxicity and increases antitumor effect. The effect of disulfiram rescue upon cisplatin pharmacokinetics and toxicity was also studied in patients with encouraging results. Selective chemical and temporal modification of various cisplatin toxicities may serve as a model for the manipulation of therapeutic indices of other toxic yet active drugs.
顺铂尿药代动力学和肾毒性：常见的昼夜节律机制。
DOI：
--
发表时间：
1982
期刊：
Cancer treatment reports
影响因子：
--
作者：
Levi,F;Hrushesky,WJ;Borch,RF;Pleasants,ME;Kennedy,BJ;Halberg,F
通讯作者：
Halberg,F
影响因子：
5.9
作者：
HRUSHESKY, WJM;SHIMP, W;KENNEDY, BJ
通讯作者：
KENNEDY, BJ