Study by HPLC-MS of the interaction of platinum antitumor complexes with potato carboxypeptidase inhibitor (PCI).
The interaction of the well-known antitumor drug cisplatin cis-[PtCl(2)(NH(3))(2)] and the compound trans-[PtCl(2)NH(3)(4-hydroxymethylpyridine)] with the small protein potato carboxypeptidase inhibitor (PCI) and a PCI mutant in which glycine-39 was substituted by methionine has been followed by HPLC/mass spectrometry. Our results showed that both Pt drugs were able to bind PCI through Met-39 and histidines in mutated PCI, whereas only the trans complex interacted significantly with wild PCI. In the cytotoxic studies, the monofunctional adduct PCI-Met-cisplatin was neither more active nor more selective than cisplatin itself when tested against three tumor cell lines with different number of EGF receptors. Those results suggested that the poor activity of the adduct could be just due to the small fraction of cisplatin which was decoordinated from the adduct and able to penetrate the tumor cells, as well as to the changes in the structure of the platinum drug after the loss of NH(3) groups upon binding PCI-Met.
Departament de Química Inorgànica, Universitat de Barcelona, Martíi Franquès 1-11, 08028 Barcelona, Spain.
Alberto
A
Martínez
Virtudes
V
Moreno
Laura
L
Sanglas
Rafael
R
de Llorens
Francesc X
FX
Avilés
Julia
J
Lorenzo
D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D013058:Mass Spectrometry; D008715:Methionine; D009154:Mutation; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000494:pharmacology; D010940:Plant Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011480:Protease Inhibitors; D011485:Protein Binding / Q000235:genetics; D011198:Solanum tuberosum
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010940:Plant Proteins; D011480:Protease Inhibitors; D008715:Methionine; D002268:Carboxypeptidases; D002945:Cisplatin