Gondal J A, Preuss H G, Swartz R, Rahman A
Department of Medicine, Georgetown University Medical Center, Lombardi Cancer Research Center, Washington, D.C. 20007.
Eur J Cancer. 1993;29A(11):1536-42. doi: 10.1016/0959-8049(93)90290-v.
The systemic toxicity and efficacy of cisplatin (CDDP) were examined in vitro and in vivo. Procedures were performed before and after the antineoplastic agent was encapsulated into multilamellar liposomes (L-CDDP). In vitro cytotoxicity evaluation in L1210 murine leukaemia and NIH OVCAR human ovarian cancer cells showed IC50 values of 0.14 and 0.05 micrograms/ml with CDDP or L-CDDP, respectively. In vivo, mice injected intravenously with L-CDDP had plasma levels of platinum 4-fold higher than with CDDP. The t1/2 alpha was 2 h and the t1/2 beta exceeded 48 h with L-CDDP; whereas a t1/2 alpha of 15 min and t1/2 beta of 12 h was observed with CDDP. The values of platinum in liver, spleen, kidneys, lungs and heart were substantially higher in L-CDDP-treated compared to CDDP-treated mice. Cytotoxic evaluation of both agents was tested in vitro (murine L1210 leukaemia and NIH OVCAR cell line) and in vivo (male CD2F1 mice). CDDP and L-CDDP showed similar cytotoxicity in tissue culture. At the highest dose given, 12 mg/kg intraperitoneally (i.p.), L-CDDP showed higher antitumour efficacy demonstrated by an increased life span of the mice. The CDDP treatment at the highest dose was lethal to all the tumour bearing mice. The nephrotoxicity in rats (blood urea nitrogen and creatinine evaluation) of L-CDDP administered i.p. was significantly less than with CDDP. In addition, the ability of kidney slices to transport organic anions [para-aminohippurate (PAH)] and consume O2 was substantially decreased in rats treated with free CDDP compared to L-CDDP. Accordingly, the liposomal encapsulation of CDDP attenuates its nephrotoxicity, but allows maintenance of antitumour efficacy and may be a potentially effective modality in clinical settings.
在体外和体内研究了顺铂（CDDP）的全身毒性和疗效。在将抗肿瘤药物包封到多层脂质体（L-CDDP）之前和之后进行了相关操作。对L1210小鼠白血病细胞和NIH OVCAR人卵巢癌细胞进行的体外细胞毒性评估显示，CDDP和L-CDDP的IC50值分别为0.14和0.05微克/毫升。在体内，静脉注射L-CDDP的小鼠血浆铂水平比注射CDDP的小鼠高4倍。L-CDDP的α半衰期为2小时，β半衰期超过48小时；而CDDP的α半衰期为15分钟，β半衰期为12小时。与CDDP处理的小鼠相比，L-CDDP处理的小鼠肝脏、脾脏、肾脏、肺和心脏中的铂含量显著更高。在体外（小鼠L1210白血病和NIH OVCAR细胞系）和体内（雄性CD2F1小鼠）对两种药物的细胞毒性进行了评估。CDDP和L-CDDP在组织培养中显示出相似的细胞毒性。以最高剂量12毫克/千克腹腔注射（i.p.）时，L-CDDP显示出更高的抗肿瘤疗效，表现为小鼠寿命延长。最高剂量的CDDP处理对所有荷瘤小鼠都是致命的。腹腔注射L-CDDP的大鼠的肾毒性（血尿素氮和肌酐评估）明显低于CDDP。此外，与L-CDDP相比，游离CDDP处理的大鼠肾切片转运有机阴离子[对氨基马尿酸（PAH）]和消耗氧气的能力大幅下降。因此，CDDP的脂质体包封可减轻其肾毒性，但能维持抗肿瘤疗效，可能是临床环境中一种潜在有效的治疗方式。
