Preclinical efficacy of a carboxylesterase 2-activated prodrug of doxazolidine.

Barthel BL, Zhang Z, Rudnicki DL, Coldren CD, Polinkovsky M, Sun H, Koch GG, Chan DC, Koch TH
J Med Chem. 2009 52 (23): 7678-88

PMID: 19634903 · PMCID: PMC2788667 · DOI:10.1021/jm900694z

Doxazolidine (Doxaz) is a functionally distinct formaldehyde conjugate of doxorubicin (Dox) that induces cancer cell death in Dox-sensitive and resistant cells. Pentyl PABC-Doxaz (PPD) is a prodrug of Doxaz that is activated by carboxylesterase 2 (CES2), which is expressed by liver, non-small-cell lung, colon, pancreatic, renal, and thyroid cancer cells. Here, we demonstrate that in two murine models, PPD was effective at slowing tumor growth and demonstrated markedly reduced cardiotoxic and nephrotoxic effects, as well as better tolerance, relative to Dox. Hepatotoxicity, consistent with liver expression of the murine CES2 homologue, was induced by PPD. Unlike irinotecan, a clinical CES2-activated prodrug, PPD produced no visible gastrointestinal damage. Finally, we demonstrate that cellular response to PPD may be predicted with good accuracy using CES2 expression and Doxaz sensitivity, suggesting that these metrics may be useful as clinical biomarkers for sensitivity of a specific tumor to PPD treatment.

MeSH Terms (19)

Animals Antineoplastic Agents Blotting, Western Carbamates Carboxylesterase Cell Line, Tumor Cell Proliferation Doxorubicin Drug Evaluation, Preclinical Female Gene Expression Regulation, Enzymologic Humans Mice Myocytes, Cardiac Neoplasms Oxazoles Prodrugs Rats Regression Analysis

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