title: Proline analogue of melphalan as a prolidase-convertible pro-drug in breast cancer MCF-7 cells.
abstract: Prolidase [E.C.3.4.13.9] is ubiquitously distributed cytosolic egzopeptidase that is known to cleave imido-bond of some low molecular weight compounds coupled to L-proline. Previously we have found that conjugation of antineoplastic drug--melphalan (Mel) with proline (pro) through imido-bond resulted in formation of a good substrate for purified prolidase. Cytosolic location of prolidase in neoplastic cells suggests that proline analogue of melphalan (Mel-pro) may serve as a prolidase convertable pro-drug. We have compared several aspects of pharmacologic actions of Mel and Mel-pro in breast cancer MCF-7 cells. It has been found that Mel-pro is more effectively transported into the MCF-7 cells, evokes higher cytotoxicity, lower antimitotic activity and collagen-inhibiting activity, compared to Mel. The results suggest that targeting of prolidase as a pro-drug-converting enzyme may serve as a potential strategy in pharmacotherapy of breast cancer.
authors.affiliation: Department of Medicinal Chemistry, Medical Academy, Białystok, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Chrzanowski
authors.forename: J
authors.initials: J
authors.lastname: Pałka
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000494:pharmacology*; D001943:Breast Neoplasms; D004150:Dipeptidases / Q000737:chemistry*; D005260:Female; D006801:Humans; D008558:Melphalan / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology; D011392:Proline / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D011355:Prodrugs; D011392:Proline; D004150:Dipeptidases; C022449:proline dipeptidase; D008558:Melphalan