Preclinical efficacy of a carboxylesterase 2-activated prodrug of doxazolidine.
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.
Barthel
Benjamin L
BL
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309, USA.
Zhang
Zhiyong
Z
Rudnicki
Daniel L
DL
Coldren
Christopher D
CD
Polinkovsky
Margaret
M
Sun
Hengrui
H
Koch
Gary G
GG
Chan
Daniel C F
DC
Koch
Tad H
TH
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D015153:Blotting, Western; D002219:Carbamates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D043182:Carboxylesterase / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D010080:Oxazoles / Q000378:metabolism* / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D012044:Regression Analysis
D000970:Antineoplastic Agents; D002219:Carbamates; D010080:Oxazoles; D011355:Prodrugs; C545998:doxazolidine; C517056:pentyl 4-(N-doxazolidinylcarbonyloxymethyl)phenylcarbamate; D004317:Doxorubicin; D043182:Carboxylesterase