Steerenberg P A, Storm G, de Groot G, Claessen A, Bergers J J, Franken M A, van Hoesel Q G, Wubs K L, de Jong W H
Laboratory for Pathology, National Institute of Public Health and Environmental Protection (NIPHEP), Bilthoven, The Netherlands.
Cancer Chemother Pharmacol. 1988;21(4):299-307. doi: 10.1007/BF00264195.
In this study we have investigated the use of liposomes as a drug carrier system for cis-diamminedichloroplatinum(II) (cis-DDP) in order to reduce the nephrotoxicity with preservation of antitumor activity. Liposomes (PC/PS/Chol 10:1:4) were prepared using hydration media containing no or a relatively low concentration of NaCl. It was found that cis-DDP containing liposomes (lip cis-DDP) injected i.v. to IgM immunocytoma-bearing LOU/M rats at a dose of 1 mg cis-DDP/kg (cumulative dose 7 mg cis-DDP/kg) showed less antitumor activity than the free drug. The optimal cumulative dose of free cis-DDP for induction of antitumor activity in this tumor system is 7 mg/kg (7 X 1 mg/kg). At a dose of 2 mg lip cis-DDP/kg (cumulative dose 14 mg cis-DDP/kg) the antitumor activity could not be increased by choosing another phospholipid composition of the liposomes [DPPC/DPPG/Chol (10:1:10)]. cis-DDP incorporated in DPPC/DPPG/Chol liposomes showed a similar antitumor activity to cis-DDP incorporated in PC/PS/Chol liposomes. After an i.v. dose of 2 mg lip cis-DDP/kg (PC/PS/Chol) kidney damage was less compared to the treatment with free cis-DDP (1 mg/kg). However, after a single dose of 2 mg cis-DDP/kg or a cumulative dose of 8 or 16 mg cis-DDP/kg, kidneys of rats treated with lip cis-DDP contained twice as much Pt as after treatment with free cis-DDP. Moreover, after treatment with lip cis-DDP, a twofold increase of the amount of Pt in tumor tissue was measured. In vitro studies with Pt recovered from spleens obtained from rats treated with lip cis-DDP i.v. showed that based on the equal amounts of Pt recovered the antitumor activity of the recovered Pt was reduced, indicating inactivation of cis-DDP in vivo. As during treatment with free cis-DDP, recurrence of the tumor was observed during the continued treatment with lip cis-DDP. It was found that these recurrent tumors were resistant to further therapy with cis-DDP. In conclusion, cis-DDP encapsulation into liposomes decreased the nephrotoxicity. The antitumor activity of cis-DDP is preserved by liposome encapsulation when it was used at a dose of 2 mg/kg, but it was reduced in terms of earlier onset of regrowth.
在本研究中，我们研究了脂质体作为顺二氯二氨铂（II）（顺铂）的药物载体系统的应用，以降低肾毒性并保留抗肿瘤活性。使用不含或含有相对低浓度氯化钠的水合介质制备脂质体（PC/PS/胆固醇10:1:4）。结果发现，以1mg顺铂/kg的剂量静脉注射含顺铂的脂质体（脂质体顺铂）给携带IgM免疫细胞瘤的LOU/M大鼠（累积剂量7mg顺铂/kg），其抗肿瘤活性低于游离药物。在该肿瘤系统中诱导抗肿瘤活性的游离顺铂的最佳累积剂量为7mg/kg（7×1mg/kg）。以2mg脂质体顺铂/kg的剂量（累积剂量14mg顺铂/kg），通过选择脂质体的另一种磷脂组成[二棕榈酰磷脂酰胆碱/二棕榈酰磷脂酰甘油/胆固醇（10:1:10）]，抗肿瘤活性无法提高。掺入二棕榈酰磷脂酰胆碱/二棕榈酰磷脂酰甘油/胆固醇脂质体中的顺铂显示出与掺入PC/PS/胆固醇脂质体中的顺铂相似的抗肿瘤活性。静脉注射2mg脂质体顺铂/kg（PC/PS/胆固醇）后，与游离顺铂（1mg/kg）治疗相比，肾脏损伤较小。然而，在单次剂量2mg顺铂/kg或累积剂量8或16mg顺铂/kg后，脂质体顺铂治疗的大鼠肾脏中的铂含量是游离顺铂治疗后的两倍。此外，脂质体顺铂治疗后，肿瘤组织中铂的含量增加了两倍。对从静脉注射脂质体顺铂治疗的大鼠脾脏中回收的铂进行的体外研究表明，基于回收的等量铂，回收的铂的抗肿瘤活性降低，表明顺铂在体内失活。正如在游离顺铂治疗期间一样，在脂质体顺铂持续治疗期间观察到肿瘤复发。发现这些复发性肿瘤对顺铂的进一步治疗具有抗性。总之，将顺铂封装到脂质体中可降低肾毒性。当以2mg/kg的剂量使用时，脂质体封装可保留顺铂的抗肿瘤活性，但就肿瘤再生的早期发生而言，其抗肿瘤活性降低。
