Colbern G T, Dykes D J, Engbers C, Musterer R, Hiller A, Pegg E, Saville R, Weng S, Luzzio M, Uster P, Amantea M, Working P K
SEQUUS Pharmaceuticals, Inc., Menlo Park, California 94025, USA.
Clin Cancer Res. 1998 Dec;4(12):3077-82.
The topoisomerase I inhibitor GL147211C [7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-campto thecin trifluoroacetate], a camptothecin analogue, has significant activity in tumor cell cytotoxicity assays in vitro and antitumor activity in both animal tumor models and human patients. Its toxicity is significant, however, effectively limiting the amount of drug that can be administered and its clinical utility. To determine whether the therapeutic index of GL147211C could be improved, the drug was encapsulated in long-circulating, pegylated (STEALTH) liposomes (SPI-355). The pharmacokinetics and antitumor activity of SPI-355 were compared to those of nonliposomal GL147211C. The plasma pharmacokinetics of SPI-355 in rats were typical of those of other pegylated liposomal formulations, with significantly increased blood circulation time; the dose-corrected area under the curve and Cmax of SPI-355 (10 mg/kg) were 1250- and 35-fold higher, respectively, than those of nonliposomal GL14711C (8.72 mg/kg). The comparative antitumor activity of SPI-355 and nonliposomal GL1472211C was evaluated in nude mice implanted with HT29 colon carcinoma xenografts. SPI-355 was 20-fold more effective than GL147211C in inhibiting tumor growth (1 mg/kg SPI-355 and 20 mg/kg GL147211C) and produced durable complete remissions of tumors at well-tolerated dose levels that were >5-fold lower than the maximally tolerated dose of GL147211C, which induced no durable complete responses. Signs of toxicity were similar between the two drugs, but liposome encapsulation increased the toxicity of drug approximately 4-fold, with increased weight loss and several deaths with SPI-355 (5 mg/kg SPI-355 versus 20 mg/kg GL147211C). Despite the increased toxicity seen with SPI-355, the therapeutic index of the liposomal formulation was increased approximately 5-fold over that of nonliposomal GL147211C, suggesting that such a pegylated liposomal formulation could demonstrate increased therapeutic index in human patients.
拓扑异构酶I抑制剂GL147211C[7-[(4-甲基哌嗪基)甲基]-10,11-(亚乙基二氧基)-(20S)-喜树碱三氟乙酸盐]，一种喜树碱类似物，在体外肿瘤细胞细胞毒性试验中具有显著活性，在动物肿瘤模型和人类患者中均具有抗肿瘤活性。然而，其毒性较大，有效地限制了可给药的药物量及其临床应用。为了确定GL147211C的治疗指数是否可以提高，将该药物封装在长循环、聚乙二醇化（隐形）脂质体（SPI-355）中。将SPI-355的药代动力学和抗肿瘤活性与非脂质体GL147211C的进行了比较。SPI-355在大鼠体内的血浆药代动力学与其他聚乙二醇化脂质体制剂的典型药代动力学相似，血液循环时间显著延长；SPI-355（10mg/kg）的剂量校正曲线下面积和Cmax分别比非脂质体GL14711C（8.72mg/kg）高1250倍和35倍。在植入HT29结肠癌异种移植物的裸鼠中评估了SPI-355和非脂质体GL1472211C的比较抗肿瘤活性。SPI-355在抑制肿瘤生长方面比GL147211C有效20倍（1mg/kg SPI-355和20mg/kg GL147211C），并在耐受性良好的剂量水平下产生持久的肿瘤完全缓解，该剂量水平比GL147211C的最大耐受剂量低5倍以上，而GL147211C未诱导持久的完全缓解。两种药物的毒性体征相似，但脂质体封装使药物毒性增加了约4倍，SPI-355（5mg/kg SPI-355与20mg/kg GL147211C相比）导致体重减轻增加和数只死亡。尽管SPI-355的毒性增加，但脂质体制剂的治疗指数比非脂质体GL147211C提高了约5倍，这表明这种聚乙二醇化脂质体制剂在人类患者中可能显示出更高的治疗指数。
