Complexes of Serum Albumin and cis - Dichlorodiammineplatinum ( 11 )

Human and bovine serum albumin (38-377 p ~ ) bound approximately 1 mol of platinum per mol of protein when incubated with 300 t o 600 PM cis-dichlorodiammineplatinum (11) (cis-DDP) for 6 h at 37 “C. Significantly increased binding was not demonstrated with higher concentrations of cis-DDP or longer incubation periods. Bovine albumin that was carboxamidomethylated retained 0.03-0.06 mol of sulfhydryl group/mol, compared with 0.62 mol/mol of unmodified bovine albumin, and bound 6 5 4 0 % less platinum when reacted with cis-DDP. Competition experiments were performed in which bovine or human albumin were incubated with cis-DDP and the plasma protease inhibitor, a2-macroglobulin (a2M). The albumins failed to protect a2M from the previously described inactivation by cisDDP (Gonias, S. L., and Pizzo, S. V. (1981) J. Biol. Chem 256,12478-12484), even when present at concentrations 270 times that of the protease inhibitor. Equivalent results were obtained when competition experiments were performed with cis-DDP that was preincubated in a manner that yielded large amounts of the more reactive teaquo” forms of the drug. Platinum-albumin complex was resolved from unreacted drug and incubated with a2M. Partial loss of the protease inhibitor activity was observed. Dialysis experiments showed that the complexes formed between albumin and cisDDP do not dissociate to a significant extent. It is suggested that the inactivation of azM by the platinumalbumin complex may involve direct reaction of the protease inhibitor with the complex.