Combination treatment of PKD utilizing dual inhibition of EGF-receptor activity and ligand bioavailability.

Abstract

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.

• Authors: William E Sweeney Jr, Kiyoshi Hamahira, Jennifer Sweeney, Michelle Garcia-Gatrell, Philip Frost, Ellis D Avner
• Journal: Kidney international (Kidney Int) Vol. 64 Issue 4 Pg. 1310-9 (Oct 2003) ISSN: 0085-2538 [Print] United States
• PMID: 12969149 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Aminoquinolines
• Aniline Compounds
• Hydroxamic Acids
• Ligands
• Organic Chemicals
• Sulfonamides
• WTACE2 compound
• ErbB Receptors
• EKB 569

Topics

• Aminoquinolines
• Aniline Compounds
• Animals
• Biological Availability
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Therapy, Combination
• ErbB Receptors (antagonists & inhibitors)
• Hydroxamic Acids (administration & dosage, adverse effects, therapeutic use, toxicity)
• Kidney (diagnostic imaging, drug effects, pathology)
• Ligands
• Mice
• Mice, Inbred BALB C
• Organic Chemicals (administration & dosage, adverse effects, therapeutic use, toxicity)
• Polycystic Kidney, Autosomal Recessive (diagnostic imaging, drug therapy, pathology)
• Sulfonamides (administration & dosage, adverse effects, therapeutic use, toxicity)
• Ultrasonography