In vitro    and in vivo evaluation of a doxorubicin prodrug that is cleaved by prostate-specific antigen Free

4725

Metastasized prostate cancer does not respond well to chemotherapy. In the present work we set out to develop a low-molecular weight prodrug of doxorubicin that is cleaved by prostate-specific antigen (PSA). PSA is a serine protease that is over-expressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. Based on our work with the albumin-binding doxorubicin prodrug EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO [DOXO = doxorubicin, EMC = ϵ-maleimidocaproic acid] which showed selective antitumor activity in a PSA-positive xenograft model (CWR22) [1], we developed a low-molecular weight prodrug with the structure Ac-Ser-Ser-Tyr-Tyr-Ser-Arg-DOXO [Ac = acetyl]. The novel prodrug of doxorubicin was efficiently cleaved by PSA at the P₁-P₁ scissile bond releasing the doxorubicin dipeptide H-Ser-Arg-DOXO which was further degraded to doxorubicin as the final cleavage product in incubation studies with prostate carcinoma (CWR22) tissue homogenate.

In vivo study with the water-soluble prodrug in the PSA-positive (CWR22) xenograft-model showed that the doxorubicin prodrug was as effective as doxorubicin at equimolar dose.

[1] F. Kratz, A. Mansour, J. Soltau, A. Warnecke, I. Fichtner, C. Unger, J. Drevs (2005): Development of albumin-binding doxorubicin prodrugs that are cleaved by prostate-specific antigen (PSA), Arch. Pharm., Pharm. Med. Chem., 338, 1-11.