Abstract #677: Design, synthesis and preclinical efficacy of a carboxylesterase 2-activated prodrug of doxazolidine: Pentyl PABC-Doxaz

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Doxazolidine (Doxaz) is the formaldehyde conjugate of doxorubicin (Dox) that induces cancer cell death in sensitive and MDR cells by cross-linking DNA. Doxaz is orders of magnitude more active than Dox but has a half-life of 3 min. under physiological conditions with respect to hydrolysis to Dox. A carboxylesterase 2-activted prodrug, pentyl PABC-Doxaz (PPD), was designed to be hydrolytically robust and to selectively deliver Doxaz to cancer cells that express the enzyme. Carboxylesterase 2 (CES2) is expressed in cytosol by liver, non-small cell lung, colon, pancreatic, renal, and thyroid cancer cells and is involved in the activation of the clinical prodrugs irinotecan and capecitabine. Cancer cell growth inhibition by PPD correlated with CES2 expression as indicated by gene array analysis. Hep G2 and N-Hep G2 hepatocarcinoma cells and H-1435 non small cell lung cancer cells were identified as highly responsive to PPD. NOD SCID mice were implanted s.c. with N-Hep G2 cells, and nude mice were implanted s.c. with H1435 cells. Tumor growth was monitored in i.v. dose escalation experiments versus no-drug and Dox controls. At termination, heart and liver sections were examined for evidence of cardio- and hepatotoxicity. Inhibition of tumor growth by PPD followed dose escalation and exceeded inhibition of tumor growth by doxorubicin near its maximum tolerated dose. In general PPD was well tolerated. Some weight loss with the maximum dose of PPD was observed at three weeks but mostly disappeared at five weeks. Heart sections of PPD-treated mice showed significantly less evidence of cardiotoxicity than heart sections of doxorubicin-treated mice. Liver sections showed more evidence of toxicity from PPD, consistent with hepatic expression of murine CES2. This study reports a strong rationale for further in vivo evaluation of PPD for treatment of tumors that express CES2. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 677.