Identification of Human Intestinal Carboxylesterase as the Primary Enzyme for Activation of a Doxazolidine Carbamate Prodrug

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• 作者：Benjamin L. Barthel ; Renee C. Torres ; Janice L. Hyatt ; Carol C. Edwards ; M. Jason Hatfield ; Philip M. Potter ; Tad H. Koch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：January 24, 2008
• 年：2008
• 卷：51
• 期：2
• 页码：298 - 304
• 全文大小：387K
• 年卷期：v.51,no.2(January 24, 2008)
• ISSN：1520-4804

文摘

Doxazolidine (Doxaz), a formaldehyde−doxorubicin (Dox) conjugate, exhibits markedly increased tumor toxicity with respect to Dox without a concurrent increase in toxicity to cardiomyocytes. Pentyl PABC-Doxaz (PPD) is a Doxaz carbamate prodrug that is hydrolyzed by carboxylesterases. Here, we identify human intestinal carboxylesterase (hiCE) as the agent of activation for PPD. Upon prodrug treatment, cells that express higher levels of hiCE responded with lower IC₅₀ values for growth inhibition. Exposing MCF-7 human breast cancer cells, which respond poorly and express little hiCE, to PPD together with hiCE resulted in a dramatic decrease in the IC₅₀, a decrease that was absent when human carboxylesterase 1 was added to prodrug treatment. Finally, U373MG glioblastoma cells overexpressing hiCE displayed ~100-fold reduction in the IC₅₀ for PPD compared to cells lacking the carboxylesterase. Overall, our studies indicate that PPD is selectively hydrolyzed to the active metabolite by hiCE.