Prostatespecific Antigenactivated Prodrugs

As the average life expectancy in the Western world increases, so does the incidence of prostate cancer. The extracellular serine protease prostate-specific antigen (PSA) is a prostate cancer-associated enzyme. PSA is produced by prostate glandular cells, whereas in the circulation this enzyme is inactivated. As a result, enzymatically active PSA is present only in prostate cancer tissue.

Substrate specificity of PSA was investigated using peptide derivatives of 7-amino-4-methylcoumarin (AMC) containing up to seven amino acids coupled via an amide bond to the peptide C-terminus. The sequence His-Ser-Ser-Lys-Leu-Gln (HSSKLQ) was selected because of specificity and serum stability (Denmeade et al., 1997). This sequence was incorporated in a hexa- or heptapeptide doxorubicin prodrug (Denmeade et al., 1998), in which the C-terminal carboxylic acid was coupled to the primary amine of doxorubicin. PSA was unable to hydrolyze the peptide bond between hexapeptide and drug. When an additional leucine (Leu) residue was incorporated between the hexapeptide and the drug, PSA was able to induce release of Leu-Dox. The heptapeptide prodrug showed in vitro selective cytotoxicity upon incubation with PSA-producing human prostate cancer cells and non-PSA-producing control cells, indicating that PSA mediated Leu-Dox release. In vivo activity was reported in nude mice bearing PSA-producing PC-82 human prostate cancer xenografts (Khan and Denmeade, 2000). The leucine-containing heptapeptide-doxorubicin derivative was less toxic than free doxorubicin and induced a more significant decrease in tumor size compared to control treatment. Leu-Dox itself has already been shown to possess activity against cancer cell lines. Also, a PSA-cleavable heptapeptide-thapsigargin conjugate proved to be a substrate for PSA. The released drug, an apoptosis-inducing agent, inhibited growth of prostate cancer xenograft tumors (Denmeade et al., 2003).

In vivo efficacy has also been obtained with the PSA-activated peptide-doxorubicin conjugate N glutaryl-(4-hydroxyprolyl)-Ala-Ser-Chg-Gln-Ser-Leu-Dox (Chg: cyclohexylglycine) (Garsky et al., 2001). PSA cleaves between the Gln and Ser residues. How the remaining residues, in particular serine, are to be removed after PSA cleavage remains unclear. The conjugate was shown to be 15 times more effective than parent doxorubicin in inhibition of growth of human prostate cancers in nude mice when both compounds were evaluated at their MTD concentration (Defeo-Jones et al., 2000). Furthermore, tumor-selective localization of doxorubicin after prodrug administration was demonstrated (Wong et al., 2001). The conjugate liberated Leu-Dox and Dox. In nude mice with tumors that did not produce PSA, the conjugate showed no significant reduction of tumor weight. A control conjugate containing a D glutamine residue was not readily cleaved by PSA.

Was this article helpful?

0 0
Delicious Diabetic Recipes

Delicious Diabetic Recipes

This brilliant guide will teach you how to cook all those delicious recipes for people who have diabetes.

Get My Free Ebook


Post a comment