Desjardins J P, Abbott E A, Emerson D L, Tomkinson B E, Leray J D, Brown E N, Hamilton M, Dihel L, Ptaszynski M, Bendele R A, Richardson F C
Gilead Sciences, Inc, 2860 Wilderness Place, Boulder, CO 80301, USA.
Anticancer Drugs. 2001 Mar;12(3):235-45. doi: 10.1097/00001813-200103000-00009.
Prolonging tumor exposure to topoisomerase I inhibitors has been correlated to enhance the efficacy of those agents. Lurtotecan, a water-soluble camptothecin analog, was formulated as a liposomal drug, NX211, to enhance the delivery of drug to tumors. Tumor-bearing mice were treated with either [14C]NX211 containing [14C]lurtotecan, [3H]NX211 containing [3H]phosphatidylcholine or [14C]lurtotecan, euthanized at selected times post-injection, and tissues, plasma, urine and feces were collected. These studies demonstrated that KB tumors of [14C]NX211-treated mice had approximately 70-fold greater concentrations of [14C]lurtotecan at 24 h, respectively, compared to concentrations of [14C]lurtotecan of the KB tumors of [14C]lurtotecan-treated mice. The area under curve (AUC) from 0 to 48 h of [14C]lurtotecan for the KB tumors of [14C]NX211-treated animals was over 17-fold greater than the AUC of [14C]lurtotecan for the tumors of [14C]lurtotecan-treated animals. Treatment with [3H]NX211 demonstrated that the lipid component continually accumulated over 24 h in the tissues. HPLC analysis of extracted material from tumors of [14C]NX211-treated mice showed that more than 95% of the radioactive material was intact [14C]lurtotecan. These findings are one of the keys justifying the development of a liposomal formulation of lurtotecan, which has the intent to increase tumor exposure and increase antitumor efficacy.
延长肿瘤对拓扑异构酶I抑制剂的暴露时间与增强这些药物的疗效相关。鲁替康，一种水溶性喜树碱类似物，被制成脂质体药物NX211，以增强药物向肿瘤的递送。给荷瘤小鼠分别用含[14C]鲁替康的[14C]NX211、含[3H]磷脂酰胆碱的[3H]NX211或[14C]鲁替康进行治疗，在注射后选定时间处死小鼠，并收集组织、血浆、尿液和粪便。这些研究表明，与用[14C]鲁替康治疗的小鼠的KB肿瘤中[14C]鲁替康的浓度相比，用[14C]NX211治疗的小鼠的KB肿瘤在24小时时[14C]鲁替康的浓度分别高约70倍。[14C]NX211治疗动物的KB肿瘤中[14C]鲁替康从0至48小时的曲线下面积（AUC）比[14C]鲁替康治疗动物的肿瘤中[14C]鲁替康的AUC大17倍以上。用[3H]NX211治疗表明脂质成分在组织中持续积累24小时。对[14C]NX211治疗小鼠的肿瘤提取物进行HPLC分析表明，超过95%的放射性物质是完整的[14C]鲁替康。这些发现是证明开发鲁替康脂质体制剂合理性的关键因素之一，其目的是增加肿瘤暴露并提高抗肿瘤疗效。
