Combination treatment of PKD utilizing dual inhibition of EGF-receptor activity and ligand bioavailability.
Combination treatment of PKD utilizing dual inhibition of EGF-receptor activity and ligand bioavailability.
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DOI：
10.1046/j.1523-1755.2003.00232.x
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发表时间：
2003-10
影响因子：
19.6
通讯作者：
W. Sweeney;Kiyoshi Hamahira;J. Sweeney;Michelle Garcia-Gatrell;P. Frost;E. Avner
中科院分区：
文献类型：
--
作者：
W. Sweeney;Kiyoshi Hamahira;J. Sweeney;Michelle Garcia-Gatrell;P. Frost;E. Avner
背景我们先前已经证明了表皮生长因子受体（EGFR）活性增加在常染色体隐性遗传性多囊肾病（ARPKD）小鼠模型（如BPK小鼠）中介导肾囊肿形成和胆管扩张（BDE）中的重要作用。本研究旨在确定（1）。如果用EGFR酪氨酸激酶活性第二代抑制剂EKB-569治疗ARPKD有效;（2）。如果酪氨酸激酶抑制剂疗法与转化生长因子-α（TGF-α）可用性的药理学降低联合使用，则使用WTACE 2可以提供改善的治疗功效和/或降低潜在毒性;和（3）.是否可以通过使用系列超声检查在鼠ARPKD模型中非侵入性地监测治疗的有效性。方法出生后7 ~ 21 d，用EKB-569腹腔注射处理BPK窝仔。EKB-569单独或与WTACE 2联合使用的有效性通过肾脏重量/体重比的降低、形态测量肾囊肿指数和肾功能评价来测量。在不同的治疗方案下，利用15 MHz线阵换能器对正常和囊性动物进行肾脏超声检查，并将超声数据与组织学和肾功能数据进行比较。结果EKB-569单独治疗BPK小鼠导致肾重/体重比显著降低，显著降低集合小管囊性指数，以及BDE，并改善肾功能。EKB-569和WTACE 2的联合治疗允许EKB-569剂量减少67%，这是达到与单独使用EKB-569产生的结果相当的结果所必需的。未处理的囊性动物平均在出生后第24天死于肾衰竭，集合小管囊性指数为4.8，BDE显著，最大尿渗透压为361 mOsm。用EKB-569和WTACE 2处理至出生后第21天的囊性动物存活良好，肾功能正常，集合小管囊性指数降低为1.7（P < 0.02），BDE改善，最大尿浓缩能力增加三倍（P < 0.01）。肾脏超声可以可靠地检测到囊性肾早在出生后第7天，自然史以及治疗干预的效果，明确划定超声评价。结论本研究证实了小鼠ARPKD（1）。EKB-569在减少囊肿形成和保护肾功能方面与第一代EGFR酪氨酸激酶抑制剂一样有效;（2）。EKB-569和WTACE 2的联合治疗在较低剂量下提供改善肾和胆异常的最大功效，从而使潜在毒性最小化;和（3）。肾脏超声提供了一种简单、可靠、非侵入性的方法来跟踪自然病程和治疗方案的效果。
BACKGROUND We have previously demonstrated an essential role for increased epidermal growth factor receptor (EGFR) activity in mediating renal cyst formation and biliary ductal ectasia (BDE) in murine models of autosomal-recessive polycystic kidney disease (ARPKD) such as the BPK mouse. The current study was designed to determine (1). if treatment with a second-generation inhibitor of EGFR tyrosine kinase activity, EKB-569, was effective in treatment of ARPKD; (2). if tyrosine kinase inhibitor therapy used in combination with pharmacologic reduction of the availability of transforming growth factor-alpha (TGF-alpha), using WTACE2, could provide improved therapeutic efficacy and/or decrease potential toxicity; and (3). if effectiveness of treatment could be monitored noninvasively in murine ARPKD models by use of serial ultrasonography. METHODS BPK litters were treated with EKB-569 by intraperitoneal injection from postnatal day 7 to postnatal day 21. EKB-569's effectiveness alone or in combination with WTACE2 was measured by reduction in kidney weight/body weight ratios, morphometric renal cystic index, and evaluation of renal function. Renal ultrasound was performed on normal and cystic animals, under different therapeutic regimens, utilizing a 15 mHz linear array transducer, and ultrasound data were compared with histology and renal functional data. RESULTS Treatment of BPK mice with EKB-569 alone resulted in a marked reduction of kidney weight/body weight ratios, dramatically reduced collecting tubule cystic index, as well as BDE, and improved renal function. The combined treatment with EKB-569 and WTACE2 permitted a 67% reduction in EKB-569 dosage necessary to achieve results equivalent to those produced with EKB-569 alone. Untreated cystic animals died of renal failure, on average, at postnatal day 24 with a collecting tubule cystic index of 4.8, significant BDE, and maximal urine osmolarity of 361 mOsm. Cystic animals treated with EKB-569 and WTACE2 to postnatal day 21 were alive and well with normal renal function, a reduced collecting tubule cystic index of 1.7 (P < 0.02), improvement in BDE, and a threefold increase in maximum urinary concentrating ability (P < 0.01). Renal ultrasound could reliably detect cystic kidneys as early as postnatal day 7 and the natural history as well as effects of therapeutic intervention were clearly delineated by ultrasound evaluation. CONCLUSION This study demonstrates that in murine ARPKD (1). EKB-569 is as effective as first-generation EGFR tyrosine kinase inhibitors in reducing cyst formation and preserving renal function; (2). combination therapy with EKB-569 and WTACE2 provides maximum efficacy in improving renal and biliary abnormalities, at lower doses, thereby minimizing potential toxicity; and (3). renal ultrasound provides a simple, reliable, noninvasive method of following natural history and effect of treatment regimens.