Significant increase in antitumor potency of doxorubicin HCl by its encapsulation in pegylated liposomes
Significant increase in antitumor potency of doxorubicin HCl by its encapsulation in pegylated liposomes
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DOI：
10.3109/08982109909035551
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发表时间：
1999-01-01
影响因子：
4.4
通讯作者：
Working, PK
中科院分区：
文献类型：
--
作者：
Colbern, GT;Hiller, AJ;Working, PK
聚乙二醇脂质体阿霉素（PL-DOX或Doxil（R））目前正在临床上用于治疗人类实体瘤（卵巢癌和乳腺癌以及卡波西肉瘤）。先前比较非脂质体阿霉素和PL-DOX的抗肿瘤活性的临床前研究已经表明，PL-DOX在等效剂量下具有显著更大的抗肿瘤活性，但是这些研究没有报道在较低剂量的PL-DOX下与脂质体包封相关的抗肿瘤效力的增加程度。本文介绍的研究旨在确定产生与非脂质体多柔比星最大耐受剂量（MTD）相同抗肿瘤活性的PL-DOX剂量。常规小鼠接种刘易斯肺或C26结肠细胞，裸鼠接种BT474或MCF 7人乳腺癌细胞。荷瘤小鼠用MTD的非脂质体多柔比星或相同或更低剂量的PL-DOX治疗。如在先前发表的研究中，在相同剂量水平下，PL-DOX具有比非脂质体阿霉素显著更大的抗肿瘤活性（p < 0.05）。在刘易斯肺癌和C26结肠癌中，非脂质体阿霉素（9 mg/kg，常规小鼠的MTD）的抗肿瘤活性相当于2 mg/kg PL-DOX的抗肿瘤活性，抗肿瘤效力增加4.5倍。在裸鼠的人乳腺癌异种移植物（BT474和MCF 7）中，非脂质体阿霉素（4 mg/kg，裸鼠的MTD）的抗肿瘤活性与2 mg/kg的PL-DOX相当，效力增加2倍。基于这些研究的结果，与非脂质体阿霉素相比，PL-DOX的效力从2倍增加到4.5倍。
Pegylated liposomal doxorubicin (PL-DOX or Doxil(R)) is currently being used in the clinic to treat solid tumors in humans (ovarian and breast cancer and Kaposi's sarcoma). Previous preclinical studies comparing the antitumor activity of nonliposomal doxorubicin and PL-DOX have shown that PL-DOX has significantly greater antitumor activity at equivalent doses, but these studies have not reported the degree of increase in antitumor potency associated with liposome encapsulation at lower doses of PL-DOX. The studies presented here were designed to determine the dose of PL-DOX that produces the same antitumor activity as the maximum tolerated dose (MTD) of nonliposomal doxorubicin. Conventional mice were inoculated with Lewis lung or C26 colon cells, and nude mice were inoculated with BT474 or MCF7 human breast cancer cells. Tumor-bearing mice were treated with nonliposomal doxorubicin at the MTD or with PL-DOX at the same or lower doses. As in previously published studies, PL-DOX had significantly greater antitumor activity than nonliposomal doxorubicin at the same dose levels (p < 0.05). In Lewis Lung and C26 Colon carcinoma, antitumor activity of nonliposomal doxorubicin (9 mg/kg, the MTD for conventional mice) was equivalent to antitumor activity of PL-DOX at 2 mg/kg, a 4.5-fold increase in antitumor potency. In human breast cancer xenografts (BT474 and MCF7) in nude mice, antitumor activity of nonliposomal doxorubicin (4 mg/kg, the MTD for nude mice) was equivalent to PL-DOX at 2 mg/kg, a 2-fold increase in potency. Based on results of these studies, the potency of PL-DOX is increased from 2- to 4.5-fold compared to nonliposomal doxorubicin.