Subcutaneous 5-azacitidine treatment of naturally occurring canine urothelial carcinoma: A novel epigenetic approach to human urothelial carcinoma drug development

Noah M. Hahn, Patty L. Bonney, Deepika Dhawan, David R. Jones, Curtis Balch, Zhongmin Guo, Corie Hartman-Frey, Fang Fang, Heidi G. Parker, Erika M. Kwon, Elaine A. Ostrander, Kenneth P. Nephew, Deborah W. Knapp

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Purpose: We determined the efficacy, biological activity, pharmacokinetics and safety of the hypomethylating agent 5-azacitidine (Celgene Corp., Summit, New Jersey) in dogs with naturally occurring invasive urothelial carcinoma. Materials and Methods: We performed a preclinical phase I trial in dogs with naturally occurring invasive urothelial carcinoma to examine once daily subcutaneous administration of 5-azacitidine in 28-day cycles at doses of 0.10 to 0.30 mg/kg per day according to 2 dose schedules, including days 1 to 5 (28-day cohort) or days 1 to 5 and 15 to 19 (14-day cohort). Clinical efficacy was assessed by serial cystosonography, radiography and cystoscopy. Urinary 5-azacitidine pharmacokinetic analysis was also done. Pretreatment and posttreatment peripheral blood mononuclear cell and invasive urothelial carcinoma DNA, respectively, was analyzed for global and gene specific [CDKN2A (p14ARF)] methylation changes. Results: Enrolled in the study were 19 dogs with naturally occurring invasive urothelial carcinoma. In the 28-day cohort the maximum tolerated dose was 0.20 mg/kg per day with higher doses resulting in grade 3 or 4 neutropenia in 4 of 6 dogs. In the 14-day cohort the maximum tolerated dose was 0.10 mg/kg per day with grade 3 or 4 neutropenia seen in 2 of 3 dogs treated at higher doses. No grade 3 or 4 nonhematological toxicity was observed during either dosing schedule. Of 18 dogs evaluable for tumor response partial remission, stable disease and progressive disease were observed in 4 (22.2%), 9 (50.0%) and 4 (22.2%), respectively. Consistent 5-azacitidine levels (205 to 857 ng/ml) were detected in urine. Pretreatment and posttreatment methylation analysis revealed no significant correlation with clinical response. Conclusions: Subcutaneous 5-azacitidine showed promising clinical activity in a canine invasive urothelial carcinoma model, thus meriting further development in humans with urothelial carcinoma.

Original languageEnglish (US)
Pages (from-to)302-309
Number of pages8
JournalJournal of Urology
Volume187
Issue number1
DOIs
StatePublished - Jan 1 2012

Keywords

  • azacitidine
  • carcinoma
  • dogs
  • urinary bladder
  • urothelium

ASJC Scopus subject areas

  • Urology

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    Hahn, N. M., Bonney, P. L., Dhawan, D., Jones, D. R., Balch, C., Guo, Z., Hartman-Frey, C., Fang, F., Parker, H. G., Kwon, E. M., Ostrander, E. A., Nephew, K. P., & Knapp, D. W. (2012). Subcutaneous 5-azacitidine treatment of naturally occurring canine urothelial carcinoma: A novel epigenetic approach to human urothelial carcinoma drug development. Journal of Urology, 187(1), 302-309. https://doi.org/10.1016/j.juro.2011.09.010