title: Serial retrograde instillations of sustained release formulation of mitomycin C to the upper urinary tract of the Yorkshire swine using a thermosensitive polymer: Safety and feasibility.
abstract: MitoGel is a novel drug formulation intended for the treatment of upper tract urothelial cancer with proven feasibility and safety in an animal model.
  
  
  
  To evaluate the feasibility, safety, toxicokinetics, and histologic changes associated with serial retrograde MitoGel instillations to the upper urinary tract in a swine model.
  
  
  
  Overall, 27 Yorkshire swine underwent 6 once-weekly unilateral retrograde instillations of MitoGel. Doses of 14, 28, or 56-mg mitomycin C (respective concentrations of 2, 4, and 8mg/ml with 9 animals per group) were evaluated. Additionally, 6 animals received sterile water as a procedure control, and 9 received gel alone (without mitomycin C), as a vehicle control.
  
  
  
  Blood and urine samples were collected for determination of MMC toxicokinetics and for hematology, biochemistry, coagulation, and urinalysis throughout the study. Two-thirds of the cohort were euthanized 24 hours after final instillation, and one-third was euthanized 1 month after final instillation. Necropsy was performed to evaluate the histologic effects of treatments.
  
  
  
  All animals received all 6 doses of agents per protocol. No mortality, clinical adverse events, or meaningful changes in hematology, chemistry, coagulation, or urinalysis were attributable to MitoGel, RTGel alone, or water instillations. Peak plasma levels of MMC were 2 orders of magnitude less than known toxicity thresholds. MitoGel-related dose-dependent microscopic findings were seen in the treated kidneys and ureters, but were of limited severity, lacked associated clinical adverse findings, and decreased over time.
  
  
  
  Serial retrograde instillations of MitoGel to the pyelocaliceal system were technically feasible, and produced no observable adverse clinical, laboratory, or histologic effects.
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, CA. Electronic address: NDonin@mednet.ucla.edu.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Donin
authors.affiliation: UroGen Pharma Ltd., Ra'anana, Israel.
authors.forename: Dalit
authors.initials: D
authors.lastname: Strauss-Ayali
authors.affiliation: UroGen Pharma Ltd., Ra'anana, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Agmon-Gerstein
authors.affiliation: UroGen Pharma Ltd., Ra'anana, Israel.
authors.forename: Nadav
authors.initials: N
authors.lastname: Malchi
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, CA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Lenis
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, CA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Holden
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, CA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Pantuck
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, CA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA.
authors.forename: Arie S
authors.initials: AS
authors.lastname: Belldegrun
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, CA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA.
authors.forename: Karim
authors.initials: K
authors.lastname: Chamie
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D003692:Delayed-Action Preparations / Q000378:metabolism / Q000494:pharmacology; D005240:Feasibility Studies; D005260:Female; D007322:Instillation, Drug; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D016685:Mitomycin / Q000378:metabolism / Q000494:pharmacology*; D011108:Polymers / Q000494:pharmacology*; D013552:Swine; D066007:Toxicokinetics; D014513:Ureter / Q000187:drug effects / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D011108:Polymers; D016685:Mitomycin
keywords: Animal; Carcinoma; Hydrogel; Mitomycin; Models; Swine; Transitional cell