Inhibitor Report for: cis-Diamminediaquaplatinum

The present work addresses the analyses of some novel kinetic parameters (k(t), K(v), t50, K(ir), t(c), m(c), IC50, IC99 and Ki) of human erythrocyte membrane-bound acetylcholinesterase (AChE, EC 3.1.1.7) inhibition by cis-diamminediaquaplatinum II (PDC). PDC is under a clinical trial for use as an antineoplastic drug. The authors recently reported that PDC and cisplatin have the ability to inhibit AChE activity in vitro. Therefore this study was designed to determine the estimation of time constant (k(t)), velocity constant (K(v)), 50% inhibition time (t50), inhibition rate constant (K(ir)), transition concentration (t(c)), meeting concentration (m(c)), 50% inhibition (IC50), 99% inhibition (IC99) and inhibition constant (Ki) by novel methods. The details are described in the text.

The present work addresses the estimation and mode of aquiring fifty per cent inhibition of human erythrocyte membrane-bound acetylcholinesterase (AChE, EC 3.1.1.7) by cis-diamminediaqua-platinum II (DDP), which is presently in clinical trials for use as an antineoplastic drug. It has been recently reported that cisplatin itself has the ability to inhibit the AChE activity in vitro [Al-Jafari, et al, 1995; Kamal and Al-Jafari, 1996]. Therefore, this study was focused on the estimation of the IC50 of AChE inhibition by DDP, and its correlation with reaction times. It was found that 0.0-20.0% and 53.8-94.5% AChE inhibition takes place at 3.0 to 60 minutes after 0.025 and 0.40 mM DDP administration, respectively. The IC50 was proportional to the reaction period, and gave values of 0.057 to 0.918 mMat reaction times ranging from 3.0 to 60.0 minutes, respectively. The DDP has 1025 and 67 times higher inhibitory potency than cisplatin for human erythrocyte AChE at 3.0 and 60.0 minutes reaction time respectively. In the light of these findings, particular attention should be paid to DDP in tumor therapy and its inhibitory effect on AChE must be considered during the decision whether to use it as an antineoplastic drug.

This work addresses the kinetic studies for the interaction of cis-diamminediaquaplatinum (II) cis-[Pt(NH3)2(H2O)2]2+, (DDP) with human erythrocyte acetylcholinesterase (AChE). The Ks for the hydrolysis of acetylthiocholine iodide (ASCh) by AChE was 0.077 mM in the control system, the value decreased by 14-38% in the DDP treated systems. The Vmax was 1.34 mumole/min/mg protein for the control system while it was decreased by 26-57% in the DDP treated systems. The Lineweaver-Burk plot, Dixon plot and their secondary replots indicated that the nature of the inhibition was of the linear mixed type, i.e. uncompetitive and noncompetitive. The values of Ki and Ki were estimated as 0.203 and 0.096 mM, respectively. The estimated values of Ki and KI in the present investigation were compared with reported values for human erythrocyte and camel retina AChE inhibition by some antineoplastic drugs: cisplatin, cyclophosphamide and methotrexate.