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 Nephew, Deborah W. Knapp

Research output: Contribution to journalArticle

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

Fingerprint

Azacitidine
Epigenomics
Canidae
Dogs
Carcinoma
Pharmaceutical Preparations
Maximum Tolerated Dose
Neutropenia
Methylation
Appointments and Schedules
Pharmacokinetics
Tumor Suppressor Protein p14ARF
p16 Genes
Cystoscopy
Human Development
Radiography
Blood Cells
Urine
Safety
DNA

Keywords

  • azacitidine
  • carcinoma
  • dogs
  • urinary bladder
  • urothelium

ASJC Scopus subject areas

  • Urology

Cite this

Subcutaneous 5-azacitidine treatment of naturally occurring canine urothelial carcinoma : A novel epigenetic approach to human urothelial carcinoma drug development. / Hahn, Noah M.; Bonney, Patty L.; Dhawan, Deepika; Jones, David R.; Balch, Curtis; Guo, Zhongmin; Hartman-Frey, Corie; Fang, Fang; Parker, Heidi G.; Kwon, Erika M.; Ostrander, Elaine A.; Nephew, Kenneth; Knapp, Deborah W.

In: Journal of Urology, Vol. 187, No. 1, 01.2012, p. 302-309.

Research output: Contribution to journalArticle

Hahn, NM, Bonney, PL, Dhawan, D, Jones, DR, Balch, C, Guo, Z, Hartman-Frey, C, Fang, F, Parker, HG, Kwon, EM, Ostrander, EA, Nephew, K & Knapp, DW 2012, 'Subcutaneous 5-azacitidine treatment of naturally occurring canine urothelial carcinoma: A novel epigenetic approach to human urothelial carcinoma drug development', Journal of Urology, vol. 187, no. 1, pp. 302-309. https://doi.org/10.1016/j.juro.2011.09.010
Hahn, Noah M. ; Bonney, Patty L. ; Dhawan, Deepika ; Jones, David R. ; Balch, Curtis ; Guo, Zhongmin ; Hartman-Frey, Corie ; Fang, Fang ; Parker, Heidi G. ; Kwon, Erika M. ; Ostrander, Elaine A. ; Nephew, Kenneth ; Knapp, Deborah W. / Subcutaneous 5-azacitidine treatment of naturally occurring canine urothelial carcinoma : A novel epigenetic approach to human urothelial carcinoma drug development. In: Journal of Urology. 2012 ; Vol. 187, No. 1. pp. 302-309.
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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.",
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AU - Jones, David R.

AU - Balch, Curtis

AU - Guo, Zhongmin

AU - Hartman-Frey, Corie

AU - Fang, Fang

AU - Parker, Heidi G.

AU - Kwon, Erika M.

AU - Ostrander, Elaine A.

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N2 - 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.

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