Conover C D, Greenwald R B, Pendri A, Shum K L
Camptothecin delivery systems: the utility of amino acid Research and Development, Enzon Inc., Piscataway, NJ 08854-3969, USA.
Anticancer Drug Des. 1999 Dec;14(6):499-506.
The primary purpose of this study was to screen individual amino acid spacers in polyethylene glycol (PEG) conjugated camptothecin for their impact on the conjugates' antitumor activity. Secondly, an active member of this series was used to assess the PEG-camptothecin conjugate's efficacy against a battery of solid tumor types. PEG-camptothecin is a novel water soluble transport form (macromolecular prodrug) of the naturally derived antitumor drug, 20-(S)-camptothecin (CPT). Rates of hydrolysis were studied in phosphate buffered saline (PBS) and the plasma of both rats and humans. In vivo efficacy screens were performed against P388/0 murine leukemia and LS174T human colon solid tumor xenograft models. The results showed that while all the derivatives had considerable stability in PBS, their rates of hydrolysis varied in both rat and human plasma according to the amino acid spacer employed. Not surprisingly, changing the amino acid also affected in vivo toxicity and efficacy in the treatment of ascites and solid tumors. A representative of this amino acid series, PEG-alanine-CPT, which showed moderate activity in the solid tumor screen, was chosen for evaluation of efficacy across a wide range of solid tumor types and demonstrated significant antitumor activity (% T/C < 30%) in all tested xenograft models (colon, ovarian, mammary, lung, pancreatic and prostate). Therefore, this study showed that the use of specific amino acid spacers affected both the PEG-camptothecin conjugates' breakdown and biological activity. We anticipate that using these insights, this soluble macromolecular transport technology could be successfully employed with a number of antitumor drugs.
本研究的主要目的是筛选聚乙二醇（PEG）偶联喜树碱中的单个氨基酸间隔基，以考察其对偶联物抗肿瘤活性的影响。其次，使用该系列中的一个活性成员评估PEG-喜树碱偶联物对一系列实体瘤类型的疗效。PEG-喜树碱是天然衍生的抗肿瘤药物20-(S)-喜树碱（CPT）的一种新型水溶性转运形式（大分子前药）。在磷酸盐缓冲盐水（PBS）以及大鼠和人类血浆中研究了水解速率。针对P388/0小鼠白血病和LS174T人结肠实体瘤异种移植模型进行了体内疗效筛选。结果表明，虽然所有衍生物在PBS中都具有相当的稳定性，但根据所采用的氨基酸间隔基不同，它们在大鼠和人类血浆中的水解速率有所变化。不出所料，改变氨基酸也会影响治疗腹水和实体瘤时的体内毒性和疗效。该氨基酸系列的一个代表物PEG-丙氨酸-CPT在实体瘤筛选中显示出中等活性，被选用于评估对多种实体瘤类型的疗效，并在所有测试的异种移植模型（结肠、卵巢、乳腺、肺、胰腺和前列腺）中表现出显著的抗肿瘤活性（%T/C<30%）。因此，本研究表明，使用特定的氨基酸间隔基会影响PEG-喜树碱偶联物的分解和生物活性。我们预计，利用这些见解，这种可溶性大分子转运技术可以成功应用于多种抗肿瘤药物。
