Prolidase-activated prodrug for cancer chemotherapy cytotoxic activity of proline analogue of chlorambucil in breast cancer MCF-7 cells.
Although prolidase [EC 3.4.13.9] is found in normal cells, substantially increased levels are found in some neoplastic tissues. Because prolidase possesses the ability to hydrolyse imido bonds of various low molecular weight compounds coupled to L-proline, we hypothesized that coupling of L-proline through an imido bond to anticancer drugs might create prodrugs which would be locally activated by tumour-associated prolidase and consequently would be less toxic to normal cells that evoke lower prolidase activity. To test this concept we have synthesized a conjugate of chlorambucil-proline (CH-pro) as a possible prodrug. Treatment of this prodrug with prolidase generated the L-proline and the free drug, demonstrating its substrate susceptibility to prolidase. We have compared several aspects of biological actions of chlorambucil (CH) and its prodrug in breast cancer MCF-7 cells. IC50 values for chlorambucil and for CH-pro in DNA synthesis were found to be 54 and 16 microM, respectively. CH-pro also exhibited a lesser ability to inhibit collagen biosynthesis in breast cancer MCF-7 cells compared to the free drug. The IC50 values for chlorambucil and for CH-pro in collagen biosynthesis were found to be about 32 and 80 microM, respectively. This suggests that the targeting of prolidase may serve as a potential strategy for converting antineoplastic prodrugs.
Bielawska
A
A
Department of Medicinal Chemistry and Drug Technology, Medical Academy of Białystok, Poland. kbiel@amb.ac.bialystok.pl
Bielawski
K
K
Chrzanowski
K
K
Wołczyński
S
S
D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000378:metabolism*; D001711:Biotransformation; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil / Q000008:administration & dosage / Q000378:metabolism*; D003094:Collagen / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004150:Dipeptidases / Q000378:metabolism*; D005260:Female; D006801:Humans; D011355:Prodrugs / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; D011355:Prodrugs; D002699:Chlorambucil; D003094:Collagen; D004150:Dipeptidases; C022449:proline dipeptidase