Wente Moritz N, Kleeff Jörg, Büchler Markus W, Wanders Jantien, Cheverton Peter, Langman Stephen, Friess Helmut
Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
Invest New Drugs. 2005 Aug;23(4):339-47. doi: 10.1007/s10637-005-1442-2.
DE-310 is composed of the topoisomerase-I-inhibitor DX-8951 (exatecan) and a biodegradable macromolecular carrier, which are covalently linked by a peptidyl spacer. In pre-clinical studies, high levels and prolonged retention of conjugated DX-8951 (carrier-bound DX-8951) have been observed in tumor tissues following DE-310 administration. This phenomenon is explained as the enhanced permeability and retention (EPR) effect. DX-8951 and G-DX-8951 (glycyl-DX-8951) exerting anti-tumor activity in vivo are released from DE-310 by enzymatic cleavage of the spacer.
To quantify the concentration of conjugated DX-8951, DX-8951 and G-DX-8951 in human tissues, six patients with different solid tumor types received 6.0 mg/m(2) of DE-310 (as equivalent of DX-8951) as a single three-hour infusion administered 7 days (+/-2 days) prior to scheduled tumor resection. Drug concentrations were then determined in the resected tissues. To evaluate the plasma PK of DE-310, plasma samples were taken up to 42 days post dosing.
There were no severe side effects of the DE-310 infusion. Concentrations of conjugated DX-8951, DX-8951 and G-DX-8951 were in general similar in tumor and relevant normal tissue samples and preferential accumulation of DE-310, DX-8951 and G-DX-8951 in human tumor tissues was not observed.
These data indicate that there is distribution of DE-310 into tissue and that DX-8951 and G-DX-8951 are released slowly over an extended period from DE-310 providing prolonged exposure similar to a continuous infusion. However, the similarity in the concentrations in tumor and relevant normal tissues does not support the EPR concept in the studied human cancers.
DE - 310由拓扑异构酶I抑制剂DX - 8951（依喜替康）和可生物降解的大分子载体组成，二者通过肽基间隔物共价连接。在临床前研究中，给予DE - 310后，在肿瘤组织中观察到结合型DX - 8951（载体结合型DX - 8951）水平较高且滞留时间延长。这种现象被解释为增强的渗透和滞留（EPR）效应。在体内发挥抗肿瘤活性的DX - 8951和G - DX - 8951（甘氨酰 - DX - 8951）通过间隔物的酶促裂解从DE - 310中释放出来。
为了定量人体组织中结合型DX - 8951、DX - 8951和G - DX - 8951的浓度，6例不同实体瘤类型的患者在预定肿瘤切除术前7天（±2天）接受6.0 mg/m²的DE - 310（以DX - 8951等效量计），单次三小时输注。然后测定切除组织中的药物浓度。为了评估DE - 310的血浆药代动力学，给药后长达42天采集血浆样本。
DE - 310输注未出现严重副作用。结合型DX - 8951、DX - 8951和G - DX - 8951在肿瘤及相关正常组织样本中的浓度总体相似，未观察到DE - 310、DX - 8951和G - DX - 8951在人体肿瘤组织中的优先蓄积。
这些数据表明DE - 310可分布到组织中，并且DX - 8951和G - DX - 8951在较长时间内从DE - 310中缓慢释放，提供了与持续输注相似的长时间暴露。然而，肿瘤组织和相关正常组织中浓度的相似性并不支持在所研究的人类癌症中的EPR概念。
