Proline analogue of melphalan as a prodrug susceptible to the action of prolidase in breast cancer MDA-MB 231 cells.

Proline analogue of melphalan (Mel-pro) was synthesized as a prodrug susceptible to the action of ubiquitously distributed, cytosolic imidodipeptidase-prolidase [E.C.3.4.13.9]. Conjugation of melphalan (Mel) with proline (Pro) through imido-bond resulted in formation of a good substrate for prolidase. Cytosolic location of prolidase in neoplastic cell suggests that proline analogue of melphalan (Mel-pro) may serve as a prolidase convertible prodrug. We have compared several aspects of pharmacologic actions of Mel and Mel-pro in estrogen-independent breast cancer MDA-MB 231 cells. It has been found that Mel-pro is more effectively transported into the MDA-MB 231 cells, evokes higher cytotoxicity, similar inhibitory effect on DNA synthesis, lower inhibitory effect on collagen biosynthesis and reduces IGF-I receptor and MAPkinase expression in MDA-MB 231 cells, compared to Mel. The results suggest that targeting of prolidase as a Mel-pro-converting enzyme may serve as a potential strategy in pharmacotherapy of breast cancer.