LIPOPHILIC CAMPTOTHECINS FOR CANCER TREATMENT

喜树碱及其类似物显示出前所未有的抗肿瘤作用 抗击多种人类癌症的活动。以确定完整日期 这些药物的治疗作用受到水溶液的限制。 其内酯环部分的不稳定性，以及这一完整性 药效团是抗肿瘤活性的基本要求.对于每个 药物环在生理条件下(即pH 7.0或 上图)，导致生物活性完全丧失。在最近 已完成调查[Burke等人，《美国化学杂志》 社会114：8318-8314，(1992)；Burke等，生物化学32：5352-5364， (1993)]，我们已经证明了脂质体结合喜树碱药物是 稳定。本文提供的脂质体稳定性数据表明，脂质体 可能作为喜树碱药物的载体，这种药物可以保存两者 内酯内酯环，增强抗肿瘤活性。本建议是一项 四年的研究旨在评估细胞药理学，血液 稳定性、抗肿瘤活性、毒性、药代动力学、器官 几种脂质体原型制剂的分布和肿瘤摄取 新合成的亲脂喜树碱。 尽管过去十年的有利结果表明，更多的 喜树碱的亲脂性类似物是最有效的化合物。 实验癌症包括多药耐药(MDR)表型，他们的 由于配方问题，进一步的开发被搁置了。 然而，我们最近的实验清楚地表明，脂质体制剂 结果既增强了药物的稳定性，又显著改善了抗肿瘤 活动。这样的方法允许脂质体既溶解又 让药物稳定下来。脂质体给药的概念是一种 耐人寻味的是，它打开了进一步发展的大门， 10，11-喜树碱等亲脂性喜树碱的评价 亚甲二氧基喜树碱比水溶性更有效和更具MDR活性 类似物，如9-氨基喜树碱、拓扑替康和CPT-11。 脂质体制剂稳定和增强体外抗肿瘤作用 喜树碱的活性；因此，它们可能对 向癌症患者介绍这类前景看好的抗癌药物。 我们建议在这里探索脂质体作为药物输送的可行性。 亲脂性类似物的载体。

Camptothecin and related analogues display unprecedented antitumor activities against a variety of human cancers. To date the full therapeutic utilities of these agents have been limited by the aqueous instability of their lactone ring moiety, with the intactness of this pharmacophore an essential requirement for antitumor activity. For each drug ring opening is rapid under physiological condiitons (i.el, pH 7.0 or above), resulting in a complete loss of biological activity. In recently completed investigations [Burke et al., Journal of the American Chemical Society 114:8318-8314, (1992); Burke et al., Biochemistry 32:5352-5364, (1993)], we have demonstrated that liposome-bound camptothecin drugs are stable. Liposome stability data presented herein suggest that liposomes may potentially serve as carriers of camptothecin drugs which conserve both lactone ring and enhance antitumor activities. The present proposal is a four-year study aimed at evaluating the cellular pharmacology, blood stability, antitumor activity, toxicity, pharmacokinetics, organ distribution and tumor uptake of several prototype liposomal preparations of newly-synthesized lipophilic camptothecins. Despite favorable findings over the past ten years indicating that the more lipophilic camptothecin analogues are the most potent compounds against experimental cancers including multidrug-resistant (MDR) phenotypes, their further development has been sidetracked due to formulation problems. However, our recent experiments clearly show that liposomal formulations result in both enhanced drug stability and marked improvements in antitumor activity. Such an approach allows the liposomes to both solubilize and stabilize the drugs. The concept of liposomal drug delivery is an intriguing one in that it opens the door to the further development and evaluation of lipophilic camptothecins such as 10,11- methylenedioxycamptothecin more potent and MDR-active than water-soluble analogues such as 9-aminocamptothecin, topotecan, and CPT-11. Liposome formulations stabilize and enhance the in vitro antitumor activities of camptothecins; thus they may be of potential utility for introducing this promising class of anticancer agents to cancer victims. We propose here to explore the feasibility of liposomes as drug delivery vehicles for lipophilic analogues.