Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer.
Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer.
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DOI：
10.1136/gutjnl-2012-302529
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发表时间：
2013-01
期刊：
影响因子：
24.5
通讯作者：
Tuveson DA
中科院分区：
文献类型：
--
作者：
Jacobetz MA;Chan DS;Neesse A;Bapiro TE;Cook N;Frese KK;Feig C;Nakagawa T;Caldwell ME;Zecchini HI;Lolkema MP;Jiang P;Kultti A;Thompson CB;Maneval DC;Jodrell DI;Frost GI;Shepard HM;Skepper JN;Tuveson DA
胰腺导管腺癌（PDA）的特点是间质纤维组织增生和血管功能障碍，严重损害药物输送。本研究探讨了丰富的细胞外基质成分，巨道尔顿糖胺聚糖透明质酸（HA），作为一种新的治疗靶点在PDA的作用。使用基因工程小鼠PDA模型，作者通过临床配制的聚乙二醇化人重组PH 20透明质酸酶（PEGPH20）酶促清除HA，并检查肿瘤灌注、血管通透性和药物递送。通过短期和生存研究评估了PEGPH20与吉西他滨联合的临床前效用。PEGPH20可快速和持续地消耗HA，诱导PDA血管的再扩张，并增加两种化疗药物多柔比星和吉西他滨的肿瘤内递送。此外，PEGPH20触发PDA肿瘤内皮细胞中的开窗和内皮间连接间隙，并促进肿瘤特异性大分子渗透性增加。最后，与吉西他滨单药治疗相比，PEGPH20和吉西他滨联合治疗可抑制PDA肿瘤生长并延长生存期，这表明其具有直接的临床效用。作者证明，HA阻碍PDA中的肿瘤内血管，并建议探索其酶耗竭作为改善胰腺癌患者药物递送和反应的一种手段。
Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies. PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine. Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility. The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.
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