Mizumura Y, Matsumura Y, Hamaguchi T, Nishiyama N, Kataoka K, Kawaguchi T, Hrushesky W J, Moriyasu F, Kakizoe T
Department of Medicine, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan.
Jpn J Cancer Res. 2001 Mar;92(3):328-36. doi: 10.1111/j.1349-7006.2001.tb01099.x.
cis-Diamminedichloroplatinum (II) (cisplatin, CDDP), a potent anticancer agent, was bound to the aspartic acid residues of poly(ethylene glycol)-poly(aspartic acid) (PEG-P(ASP)) block copolymer by ligand substitution reaction at the platinum atom of CDDP. The polymeric drug thus obtained was observed to form a micelle structure in aqueous medium, showing excellent water solubility. In the present study, in vitro and in vivo antitumor activity against several human tumor cell lines, toxicity and pharmacokinetic characteristics in rodents of CDDP-incorporated polymeric micelles (CDDP / m) were evaluated in comparison with those of CDDP. In vitro, CDDP / m exhibited 10 - 17% of the cytotoxicity of CDDP against human tumor cell lines. CDDP / m given by intravenous (i.v.) injection yielded higher and more sustained serum levels than CDDP. In vivo CDDP / m treatment resulted in higher and more sustained levels in tumor tissue than CDDP, and showed similar antitumor activity to CDDP against MKN 45 human gastric cancer xenograft. CDDP / m treatment caused much less renal damage than CDDP. These results indicate that CDDP / m treatment can reduce CDDP-induced nephrotoxicity without compromising the anticancer cytotoxicity of CDDP.
顺二氯二氨合铂（II）（顺铂，CDDP）是一种强效抗癌剂，通过在CDDP的铂原子上进行配体取代反应，与聚（乙二醇）-聚（天冬氨酸）（PEG-P（ASP））嵌段共聚物的天冬氨酸残基结合。观察到由此获得的聚合物药物在水性介质中形成胶束结构，显示出优异的水溶性。在本研究中，与CDDP相比，评估了载有CDDP的聚合物胶束（CDDP / m）对几种人类肿瘤细胞系的体外和体内抗肿瘤活性、在啮齿动物中的毒性和药代动力学特征。在体外，CDDP / m对人类肿瘤细胞系的细胞毒性为CDDP的10 - 17%。静脉注射（i.v.）给予CDDP / m产生的血清水平比CDDP更高且更持久。在体内，CDDP / m治疗导致肿瘤组织中的水平比CDDP更高且更持久，并且对MKN 45人胃癌异种移植显示出与CDDP相似的抗肿瘤活性。CDDP / m治疗引起的肾损伤比CDDP少得多。这些结果表明，CDDP / m治疗可以降低CDDP诱导的肾毒性，而不会损害CDDP的抗癌细胞毒性。
