Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT).
Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT).
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I期和药代动力学（PK）MAG-CPT研究（PNU 166148）：Camptothecin（CPT）的聚合物衍生物。
DOI：
10.1038/sj.bjc.6601922
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发表时间：
2004-07-05
影响因子：
8.8
通讯作者：
Twelves, C
中科院分区：
文献类型：
--
作者：
Bissett, D;Cassidy, J;de Bono, JS;Muirhead, F;Main, M;Robson, L;Fraier, D;Magnè, ML;Pellizzoni, C;Porro, MG;Spinelli, R;Speed, W;Twelves, C
正在开发聚合物细胞毒性缀合物，目的是优先将抗癌剂递送至肿瘤。 MAG-CPT包含与水溶性聚合物主链甲基丙烯酰甘氨酰胺连接的拓扑异构酶I抑制剂喜树碱（平均分子量18kDa，按重量计10％CPT）。晚期实体恶性肿瘤患者每 4 周输注一次 30 分钟。我们研究的目的是确定 MAG-CPT 的最大耐受剂量、剂量限制毒性以及血浆和尿液药代动力学，并记录对该治疗的反应。起始剂量为 30mgm−2（剂量以毫克当量喜树碱表示）。总共有 23 名患者接受了 6 个剂量水平的 47 个疗程，最大剂量为 240mgm−2。剂量限制性毒性包括骨髓抑制、中性粒细胞减少性败血症和腹泻。一名患者在最大剂量的第 1 周期 MAG-CPT 后死亡。最大耐受剂量和进一步临床研究推荐剂量为200mgm−2。 MAG-CPT 和释放的 CPT 的半衰期均延长（>6 天），并且治疗后 4 周从血浆和尿液中恢复到可测量的 MAG-CPT 水平。然而，随后对该药物的药效学研究导致其退出临床开发。
Polymeric cytotoxic conjugates are being developed with the aim of preferential delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I inhibitor camptothecin linked to a water-soluble polymeric backbone methacryloylglycynamide (average molecular weight 18 kDa, 10% CPT by weight). It was administered as a 30-min infusion once every 4 weeks to patients with advanced solid malignancies. The objectives of our study were to determine the maximum tolerated dose, dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document responses to this treatment. The starting dose was 30 mg m−2 (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mg m−2. Dose-limiting toxicities were myelosuppression, neutropaenic sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum dose. The maximum tolerated dose and dose recommended for further clinical study was 200 mg m−2. The half-lives of both MAG-CPT and released CPT were prolonged (>6 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4 weeks after treatment. However, subsequent pharmacodynamic studies of this agent have led to its withdrawal from clinical development.
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影响因子：
10.8
作者：
Caiolfa, VR;Zamai, M;Suarato, A
通讯作者：
Suarato, A
影响因子：
10.8
作者：
Duncan, R;Gac-Breton, S;Searle, F
通讯作者：
Searle, F
影响因子：
8.8
作者：
Schoemaker, N E;van Kesteren, C;Rosing, H;Jansen, S;Swart, M;Lieverst, J;Fraier, D;Breda, M;Pellizzoni, C;Spinelli, R;Grazia Porro, M;Beijnen, J H;Schellens, J H M;ten Bokkel Huinink, W W
通讯作者：
ten Bokkel Huinink, W W
影响因子：
3
作者：
Conover, CD;Greenwald, RB;Shum, KL
通讯作者：
Shum, KL
影响因子：
3
作者：
Sarapa, N;Britto, MR;Nygren, P
通讯作者：
Nygren, P